Superoxide radical inhibitor

ABSTRACT

A superoxide radical inhibitor containing, as an effective ingredient, an azole derivative represented by the general formula (1), ##STR1##  wherein R 1  represents a phenyl group which may have 1-3 lower alkoxy groups as substituent(s) on the phenyl ring, a phenyl group having a lower alkylenedioxy group, or the like; R 2  represents a hydrogen atom, a phenyl group, a halogen atom, a lower alkoxycarbonyl group, a lower alkyl group, an amino-lower alkyl group which may have a lower alkyl group as a substituent, a dihydrocarbostyril group, or the like; R 3  represents a group of the formula, ##STR2## (R 4B  represents a hydroxyl group, a carboxy group, a lower alkenyl group or a lower alkyl group. m represents 0, 1 or 2); X represents a sulfur atom or an oxygen atom! or a salt thereof.

This is a division of application Ser. No. 08/444,728, filed May 19,1995, allowed, which is a continuation of Ser. No. 07/916,082, filed asPCT/JP91/01659 Nov. 29, 1991, (now abandoned).

TECHNICAL FIELD

The present invention relates to a superoxide radical inhibitorcontaining an azole derivative as the effective ingredient.

BACKGROUND ART

It is thought that neutrophilic leukocytes show a germicidal activity toforeign invaders in living bodies by a wondering reaction, a feedingaction, generation of superoxide radical (O₂ ⁻) and release of lysosomalenzyme and play an important role in protection of living body. Whileneutrophilic leukocytes have the above reaction for living bodyprotection, it has been made clear that the superoxide radical releasedby tissues or neutrophilic leukocytes during ischemia of tissues andsubsequent blood re-perfusion or during acute inflammation at earlystage destroys cells, causing functional disturbances of tissues B. R.Lucchesi: Annual Review of Pharmacology and Toxicology, Vol. 26, p. 201(1986); B. A. Freeman et al.: Laboratory Investigation, Vol. 47, p. 412(1982); E. Braunwald, R. A. Kloner: Journal of Clinical Investigation,Vol. 76, p. 1713 (1985); J. L. Romson et al.: Circulation, Vol. 67, p.1016 (1983)!.

DISCLOSURE OF THE INVENTION

Based on the thought that the major cause for the above-mentioneddisturbances in cells, in particular the disturbances after ischemia andre-perfusion in heart, brain, kidney, lung and digestive tract lies inthe superoxide radical released by neutrophilic leukocytes, the presentinvention has an object of providing a new drug for inhibiting therelease of the superoxide radical.

The present inventors made study for the above object and, as a result,found that certain azole derivatives show a very strong inhibitoryactivity for release of superoxide radical in living bodies. Furtherstudy based on the finding has led to the completion of the presentinvention.

Therefore, the present invention relates to a superoxide radicalinhibitor containing, as the effective ingredient, at least one of theazole derivatives represented by the following general formula (1).

Azole derivatives represented by the general formula (1), ##STR3##{wherein R¹ and R³, which may be the same or different, each represent aphenyl group which may have 1 to 5 substituents on the phenyl ring,selected from the group consisting of an alkoxy group, a tri-lower alkylgroup-substituted silyloxy group, a lower alkyl group, a hydroxyl group,a lower alkenyloxy group, a lower alkylthio group, a phenyl group whichmay have a group selected from the group consisting of a thiazolyl grouphaving, as a substituent on the thiazolyl ring, a phenyl group which mayhave a lower alkoxy group on the phenyl ring, a carboxyl group and ahydroxyl group, a lower alkylsulfinyl group, a lower alkylsulfonylgroup, a halogen atom, a nitro group, a group of the formula, ##STR4##wherein A represents a lower alkylene group or a group of the formula##STR5## l represents 0 or 1; R⁸ and R⁹, which may be the same ordifferent, each represent a hydrogen atom, a lower alkyl group, a loweralkanoyl group, an amino-lower alkyl group which may have a lower alkylgroup as a substituent, or a piperidinyl-lower alkyl group, further R⁸and R⁹ as well as the adjacent nitrogen atom being bonded thereto,together with or without other nitrogen atom or oxygen atom may form afive- to six-membered saturated or unsaturated heterocyclic group; saidfive- to six-membered heterocyclic group may have a lower alkanoyl groupor a lower alkyl group as a substituent.!, a lower alkanoyl group, alower alkanoyloxy group, an alkoxycarbonyl group, a cyano group, atetrahydropyranyloxy group which may have 1-4 substituents selected fromthe group consisting of a hydroxyl group, a lower alkoxycarbonyl group,a phenyl-lower alkoxy group, a hydroxyl group- or lower alkanoyloxygroup-substituted lower alkyl group and a lower alkanoyloxy group, anamidino group, a hydroxysulfonyloxy group, a loweralkoxycarbonyl-substituted lower alkoxy group, a carboxy-substitutedlower alkoxy group, a mercapto group, a lower alkoxy-substituted loweralkoxy group, a lower alkyl group having hydroxyl groups, a loweralkenyl group, an aminothiocarbonyloxy group which may have a loweralkyl group as a substituent, an aminocarbonylthio group which may havea lower alkyl group as a substituent, a lower alkanoyl-substituted loweralkyl group, a carboxy group, a group of the formula, ##STR6## (R²¹ andR²² which may be the same or different, each represent a hydrogen atomor a lower alkyl group.), a phenyl-lower alkoxycarbonyl group, acycloalkyl group, a lower alkynyl group, a loweralkoxycarbonyl-substituted lower alkyl group, a carboxy-substitutedlower alkyl group, a lower alkoxycarbonyl-substituted lower alkenylgroup, a carboxy-substituted lower alkenyl group, a loweralkylsulfonyloxy group which may have a halogen atom, a loweralkoxy-substituted lower alkoxycarbonyl group, a lower alkenyl grouphaving halogen atoms and a phenyl-lower alkoxy group; a phenyl grouphaving a lower alkylenedioxy group; a 5- to 15-membered monocyclic,bicyclic or tricyclic heterocyclic residual group having 1 to 2 heteroatoms selected from the group consisting of a nitrogen atom, an oxygenatom and a sulfur atom said heterocyclic residual group may have 1 to 3substituents selected from the group consisting of an oxo group, analkyl group, a benzoyl group, a lower alkanoyl group, a hydroxyl group,a carboxy group, a lower alkoxycarbonyl group, a lower alkylthio group,a group of the formula, ##STR7## (A is the same as defined above. R²³and R²⁴, which may be the same or different, each represent a hydrogenatom or a lower alkyl group; further, R²³ and R²⁴ as well as theadjacent nitrogen atom being bonded thereto, together with or withoutother nitrogen atom or oxygen atom may form a five- to six-memberedsaturated heterocyclic group; said five- to six-membered heterocyclicgroup may have a lower alkyl group as a substituent.), a cyano group, alower alkyl group having hydroxyl groups, a phenylaminothiocarbonylgroup and an amino-lower alkoxycarbonyl group which may have a loweralkyl group as a substituent.!; a lower alkyl group; a loweralkoxycarbonyl-lower alkyl group; a lower alkoxycarbonyl group; acarbamoyl-lower alkyl group; a 2,3-dihydroindenyl group which may havean oxo group or/and a hydroxyl group as substituent(s); a phenyl-loweralkyl group which may have a lower alkoxy group as a substituent on thephenyl ring or may have a hydroxyl group as a substituent on the loweralkyl group; a benzoyl group which may have a lower alkoxy group as asubstituent on the phenyl ring; a phenyl-lower alkenyl group which mayhave a lower alkoxy group as a substituent on the phenyl ring; apiperazinyl-lower alkyl group which may have a lower alkyl group on thepiperazine ring; or an adamantyl group; R³ may represent, besides theabove, a hydrogen atom; R² represents a hydrogen atom, a phenyl group, ahalogen atom, a lower alkoxycarbonyl group, a lower alkyl group, anamino-lower alkyl group (which may have a lower alkyl group as asubstituent), or a dihydrocarbostyril group; R² and R³ may bond to eachother to form a group of the formula, ##STR8## a group of the formula,##STR9## or a group of the formula, ##STR10## X represents a sulfur atomor an oxygen atom.}, and salts thereof.

The compounds of the present invention have an activity of inhibitingthe release of superoxide radical from neutrophilic leukocytes or ofremoving the superoxide radical. Accordingly, they have an action ofpreventing or lowering the in vivo production of peroxidized lipids.Hence, the compounds are useful as an agent for preventing and treatingvarious disturbances and diseases caused by excessive generation ofsuperoxide radical, in vivo accumulation of peroxidized lipids, ordefect of protective organizations therefor. More specifically, thedrugs of the present invention are useful in a pharmaceutical field as adrug for protecting various tissue cells from disturbances associatedwith ischemia and blood reperfusion, for example, a remedy for ulcers ofthe digestive tract (e.g. stress ulcer), a remedy for ischemic heartdisease (e.g. myocardial infarction, arrhythmia), a remedy forcerebrovascular diseases (e.g. cerebral hemorrhage, cerebral infarction,temporal cerebral ischemic attack), and a hepatic and renal functionimprover for disturbances caused by transplant, microcirculationfailure, etc., or as an agent for inhibiting various cell functiondisturbances believed to be caused by the superoxide radical abnormallygenerated by factors other than ischemia, for example, a remedy forBechcet disease, dermatovascular inflammation, ulcerative colitis,malignant rheumatoid, arthritis, arteriosclerosis, diabetes mellitus,etc.

It is described in Japanese Patent Publication No. 15935/1971 that thecompounds represented by the following general formula, ##STR11##(wherein R¹ is a group selected from the group consisting of a hydrogenatom and a straight-chain or branched-chain lower alkyl group of 1 to 5carbon atoms; R² is a group selected from the group consisting of alower alkyl group having 1 to 5 carbon atoms, a phenylalkyl group whichmay be substituted with a lower alkyl or lower alkoxy group having 1 to5 carbon atoms, or substituted with one or more halogen atoms, and aphenyl group; and A is a group selected from the group consisting of ahydrogen atom, a halogen atom, a hydroxyl group and a lower alkyl orlower alkoxy group having 1 to 5 carbon atoms.) have properties whichare advantageous for fibrinolysis, platelet stickiness, ulcers andimmunological treatments and can be used for prevention and treatment ofthrombosis, arteriosclerosis, gastric ulcer and hypersecretion. Amongthe compounds of the present invention, the thiazole derivativesrepresented by the following general formula (A), ##STR12## whereinR^(A) represents a hydrogen atom or a hydroxyl group; R^(1A) and R^(2A)each represent a methoxy group or an ethoxy group; R^(3A) represents ahydrogen atom or a lower alkyl group; R^(A) is substituted at the 4- or6-position in the phenyl ring; R^(1A) and R^(2A) should not be a methoxygroup simultaneously! and their salts contain some compounds which aresimilar to the compounds of the above prior art in chemical structure;however, the compounds of the present invention are not disclosed insaid prior art. Further, the compounds of the present invention, asshown in the pharmacological tests given later in Table 16, exhibit verystrong inhibitory activities for releasing superoxide radical, eventhough as compared with the most similar compounds.

Among the compounds of the present invention, preferable are:

thiazole derivatives represented by the general formula (B), ##STR13##{wherein R^(1B) represents a phenyl group which may have 1 to 3 loweralkoxy groups as substituent(s) on the phenyl ring; a phenyl grouphaving a lower alkylenedioxy group; a pyridyl group which may have anoxo group; a thienyl group; a carbostyril group; a pyrazyl group; apyrrolyl group; a quinolyl group which may have an oxo group; or a3,4-dihydrocarbostyril group; R^(2B) represents a hydrogen atom; R^(3B)represents a group of the formula, ##STR14## R^(4B) represents an alkoxygroup; a tri-lower alkyl group-substituted silyloxy group; a lower alkylgroup; a hydroxyl group; a lower alkenyloxy group; a lower alkylthiogroup; a phenyl group which may have a group selected from the groupconsisting of a thiazolyl group having, as a substituent on thethiazolyl ring, a phenyl group which may have a lower alkoxy group onthe phenyl ring, a carboxyl group and a hydroxyl group; a loweralkylsulfinyl group; a lower alkylsulfonyl group; a halogen atom; anitro group; a group of the formula, ##STR15## (wherein A represents alower alkylene group or a group ##STR16## l represents 0 or 1; R⁸ andR⁹, are each the same or different, and are each a hydrogen atom, alower alkyl group, a lower alkanoyl group, an amino-lower alkyl groupwhich may have a lower alkyl group as a substituent, or apiperidinyl-lower alkyl group; further R⁸ and R⁹ well as the adjacentnitrogen atom being bonded thereto, together with or without othernitrogen atom or oxygen atom may form a five- to six-membered saturatedor unsaturated heterocyclic group; said five- to six-memberedheterocyclic group may have a lower alkanoyl group or a lower alkylgroup as a substituent.); a lower alkanoyl group; a lower alkanoyloxygroup; an alkoxycarbonyl group; a cyano group; a tetrahydropyranyloxygroup which may have 1-4 substituents selected from the group consistingof a hydroxyl group, a lower alkoxycarbonyl group, a phenyl-lower alkoxygroup, a lower alkanoyloxy group-substituted lower alkyl group and alower alkanoyloxy group; an amidino group; a hydroxysulfonyloxy group; alower alkoxycarbonyl-substituted lower alkoxy group; acarboxy-substituted lower alkoxy group; a mercapto group; a loweralkoxy-substituted lower alkoxy group; a lower alkyl group havinghydroxyl groups; a lower alkenyl group; an aminothiocarbonyloxy groupwhich may have a lower alkyl group as a substituent; anaminocarbonylthio group which may have a lower alkyl group as asubstituent; a lower alkanoyl-substituted lower alkyl group; a carboxygroup; a group of the formula, ##STR17## (R²¹ and R²² which may be thesame or different, each represent a hydrogen atom or a lower alkylgroup.); a phenyl-lower alkoxycarbonyl group; a cycloalkyl group; alower alkynyl group; a lower alkoxycarbonyl-substituted lower alkylgroup; a carboxy-substituted lower alkyl group; a loweralkoxycarbonyl-substituted lower alkenyl group; a carboxy-substitutedlower alkenyl group; a lower alkylsulfonyloxy group which may have ahalogen atom; a lower alkoxy-substituted alkoxycarbonyl group; a loweralkenyl group having halogen atoms; or a phenyl-lower alkoxy group. mrepresents 0, 1 or 2.!; or, a phenyl group having 1-3 substituents, onthe phenyl ring, selected from the group consisting of a loweralkanoyloxy group, a hydroxysulfonyloxy group, a cyano group, an amidinogroup, a nitro group, a lower alkylthio group, a lower alkylsulfonylgroup, a tetrahydropyranyloxy group which may have 1 to 4 substituentsselected from the group consisting of a hydroxyl group, a loweralkoxycarbonyl group, a phenyl-lower alkoxy group, a hydroxyl group- orlower alkanoyloxy group-substituted lower alkyl group and a loweralkanoyloxy group, a phenyl group which may have a group selected fromthe group consisting of a thiazolyl group which may have, as asubstituent on the thiazolyl ring, a phenyl group which may have a loweralkoxy group on the phenyl ring, a carboxyl group and a hydroxyl group,a lower alkyl group having hydroxyl groups, and a group of the formula,##STR18## (R²¹ and R²² are the same as defined above); a phenyl grouphaving a lower alkylenedioxy group; a lower alkyl group; a loweralkoxycarbonyl-lower alkyl group; a lower alkoxycarbonyl group; acarbamoyl-lower alkyl group; a 2,3-dihydroindenyl group which may havean oxo group or/and a hydroxyl group as substituent(s); a phenyl-loweralkyl group which may have a lower alkoxy group as a substituent on thephenyl ring or may have a hydroxyl ring as a substituent on the loweralkyl group; a benzoyl group which may have a lower alkoxy group as asubstituent on the phenyl ring; a phenyl-lower alkenyl group which mayhave a lower alkoxy group as a substituent on the phenyl ring; apiperazinyl-lower alkyl group which may have a lower alkyl group as asubstituent on the piperazinyl ring; or an adamantyl group. When R^(4B)represents a lower alkoxycarbonyl group-substituted lower alkyl group ora carboxy-substituted lower alkyl group, then, m represents 2}, andtheir salts;

thiazole derivatives represented by the general formula (C), ##STR19##wherein R^(1C) represents a phenyl group which may have 1 to 3 loweralkoxy groups as substituent(s) on the phenyl ring; R^(2C) represents ahydrogen atom; R^(3C) represents a group of the formula, ##STR20##(wherein R^(4C) represents a hydrogen atom, a lower alkyl group, aphenyl-lower alkyl group or a lower alkoxy-substituted lower alkylgroup; R^(5C) represents an amino group, a lower alkoxygroup-substituted lower alkyl group, a lower alkyl group, a nitro group,a lower alkenyl group, a lower alkanoyl group, a lower alkenyl grouphaving halogen atoms, a phenyl-lower alkoxy group, a halogen atom or ahydroxyl group-substituted lower alkyl group; n represents 2)!, andtheir salts;

thiazole derivatives represented by the general formula (D), ##STR21##wherein R^(1D) represents a phenyl group which may have 1 to 3 loweralkoxy groups as substituent(s) on the phenyl ring; R^(2D) represents ahydrogen atom; R^(3D) represents a group of the formula, ##STR22##(wherein R^(4D) represents a hydrogen atom or a lower alkyl group;R^(5D) represents an amino group, a lower alkoxycarbonyl-lower alkoxygroup, a nitro group, a lower alkenyloxy group, a loweralkoxy-substituted lower alkoxy group, a mercapto group, a loweralkanoyloxy group, an aminocarbonylthio group which may have a loweralkyl group as a substituent, an aminothiocarbonyloxy group which mayhave a lower alkyl group as a substituent, a carboxy-substituted loweralkoxy group or a lower alkylsulfoniumoxy group which may have a halogenatom)!, and their salts;

thiazole derivatives represented by the general formula, ##STR23##{wherein R¹ is the same as defined above; R^(2E) represents a hydrogenatom; R^(3E) represents a 5- to 15-membered monocyclic, bicyclic ortricyclic heterocyclic residual group having 1 to 2 hetero atomsselected from the group consisting of a nitrogen atom, an oxygen atomand a sulfur atom said heterocyclic residual group may have 1 to 3substituents selected from the group consisting of an oxo group, analkyl group, a benzoyl group, a lower alkanoyl group, a hydroxyl group,a carboxy group, a lower alkoxycarbonyl group, a lower alkylthio group,a group of the formula, ##STR24## (A and l are the same as definedabove; R²³ and R²⁴, are each the same or different, and are eachrepresents a hydrogen atom or a lower alkyl group; further R²³ and R²⁴as well as the adjacent nitrogen atom being bonded thereto, togetherwith or without other nitrogen atom or oxygen atom may form a five- tosix-membered saturated heterocyclic group; said five- to six-memberedheterocyclic group may have a lower alkyl group as a substituent), acyano group, lower alkyl group having hydroxy groups, a phenylamino-thiocarbonyl group and an amino-lower alkoxycarbonyl group which mayhave a lower alkyl group as a substituent!}, and their salts; and

thiazole derivatives represented by the general formula (F), ##STR25##wherein R¹ is the same as defined above; R^(2F) represents a hydrogenatom, R^(3F) represents a group of the formula, ##STR26## (wherein A, land m are the same as defined above; R^(8F) and R^(9F), which may be thesame or different, each represent a lower alkanoyl group, an amino-loweralkyl group which may have a lower alkyl group as a substituent, or apiperidinyl-lower alkyl group; further R^(8F) and R^(9F) as well as theadjacent nitrogen atom being bonded thereto, together with or withoutother nitrogen atom or oxygen atom may form a five- to six-memberedsaturated or unsaturated heterocyclic group; said five- to six-memberedheterocyclic group may have a lower alkanoyl group or a lower alkylgroup as a substituent); R^(4F) is the same as the above-mentionedR^(4B) other than a hydroxyl group)!, or their salts.

BEST MODE FOR CARRYING OUT THE INVENTION

Each group shown in the present specification is specifically asfollows.

The alkoxy group can be exemplified by straight-chain or branched-chainalkoxy groups having 1 to 18 carbon atoms such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy,heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy,tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy,octadecyloxy and the like.

The lower alkyl group can be exemplified by straight-chain orbranched-chain alkyl groups having 1 to 6 carbon atoms such as methyl,ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.

The lower alkylthio group can be exemplified by straight-chain orbranched-chain alkylthio groups having 1 to 6 carbon atoms such asmethylthio, ethylthio, propylthio, isopropylthio, butylthio,tert-butylthio, pentylthio, hexylthio and the like.

The lower alkylsulfonyl group can be exemplified by straight-chain orbranched-chain alkylsulfonyl groups having 1 to 6 carbon atoms such asmethylsulfonyl, ethylsulfonyl, isopropylsulfonyl, butylsulfonyl,tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.

As the halogen atom, there can be mentioned, for example, a fluorineatom, a chlorine atom, a bromine atom and an iodine atom.

As the lower alkanoyl group, there can be mentioned straight-chain orbranched-chain alkanoyl groups having 1 to 6 carbon atoms such asformyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl,tert-butylcarbonyl, hexanoyl and the like.

The lower alkoxycarbonyl group can be exemplified by straight-chain orbranched-chain alkoxycarbonyl groups having 1 to 6 carbon atoms such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyland the like.

As to the lower alkylenedioxy group, there can be mentionedstraight-chain or branched-chain alkylenedioxy groups having 1 to 3carbon atoms such as methylenedioxy, ethylenedioxy, trimethylenedioxy,tetramethylenedioxy and the like.

As to the alkyl group, there can be mentioned, in addition to the loweralkyl groups metnioned above, straight-chain or branched-chain alkylgroups having 1 to 18 carbon atoms such as heptyl, octyl, nonyl, decyl,undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, octadecyland the like.

As to the lower alkoxycarbonyl-lower alkyl group, there can be mentionedstraight-chain or branched-chain alkoxycarbonylalkyl groups having 1 to6 carbon atoms whose alkyl moieties are each a straight-chain orbranched-chain alkyl group having 1 to 6 carbon atoms, such asmethoxycarbonylmethyl, 3-methoxycarbonylpropyl, ethoxycarbonylmethyl,4-ethoxycarbonylbutyl, 6-propoxycarbonylhexyl,5-isopropoxycarbonylpentyl, 1,1-dimethyl-2-butoxycarbonylethyl,2-methyl-3-tert-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl,hexyloxycarbonylmethyl and the like.

As to the carbamoyl-lower alkyl group, there can be mentionedcarbamoylalkyl groups whose alkyl moieties are each a straight-chain orbranched-chain alkyl group having 1 to 6 carbon atoms, such ascarbamoylmethyl, 2-carbamoylethyl, 1-carbamoylethyl, 3-carbamoylpropyl,4-carbamoylbutyl, 5-carbamoylpentyl, 6-carbamoylhexyl,1,1-dimethyl-2-carbamoylethyl, 2-methyl-3-carbamoylpropyl and the like.

The 2,3-dihydroindenyl group which may have an oxo group or/and ahydroxyl group as substituent(s), can be exemplified by2,3-dihydroindenyl groups which may each have an oxo group or/and ahydroxyl group as substituent(s), such as1-oxo-7-hydroxy-2,3-dihydroindenyl, 1-oxo-6-hydroxy-2,3-dihydroindenyl,1-oxo-5-hydroxy-2,3-dihydroindenyl, 1-oxo-4-hydroxy-2,3-dihydroindenyl,1-oxo-2,3-dihydroindenyl, 2-oxo-2,3-dihydroindenyl,2-oxo-7-hydroxy-2,3-dihydroindenyl and the like.

The phenyl group which may have, on the phenyl ring, 1 to 5substituent(s) selected from the group consisting of an alkoxy group, atri-lower alkyl group-substituted silyloxy group, a lower alkyl group, ahydroxyl group, a lower alkenyloxy group, a lower alkylthio group, aphenyl group, a lower alkylsulfonyl group, a lower alkylsulfinyl group,a halogen atom, a nitro group, a group of the formula, ##STR27##(wherein A, l, R⁸ and R⁹ are the same as defined above), a loweralkanoyl group, a lower alkanoyloxy group, a lower alkoxycarbonyl group,a cyano group, a tetrahydropyranyloxy group which may have 1 to 4substituents selected from the group consisting of a hydroxyl group, alower alkoxycarbonyl group, a phenyl-lower alkoxy group, a loweralkanoyloxy group-substituted lower alkyl group and a lower alkanoyloxygroup, an amidino group, a hydroxysulfonyloxy group, a loweralkoxycarbonyl-substituted lower alkoxy group, a carboxy-substitutedlower alkoxy group, a mercapto group, a lower alkoxy-substituted loweralkoxy group, a lower alkyl group having hydroxyl groups, a loweralkenyl group, an aminothiocarbonyloxy group which may have a loweralkyl group as a substituent, an aminocarbonylthio group which may havea lower alkyl group as a substituent, a lower alkanoyl-substituted loweralkyl group, a carboxy group, a group of the formula, ##STR28## (R²¹ andR²², are each the same or different, and are each represents a hydrogenatom or a lower alkyl group), a phenyl-lower alkoxycarbonyl group, acycloalkyl group, a lower alkynyl group, a loweralkoxycarbonyl-substituted lower alkyl group, a carboxy-substitutedlower alkyl group, a lower alkoxycarbonyl-substituted lower alkenylgroup, a carboxy-substituted lower alkenyl group, a halogen-substitutedor unsubstituted lower alkylsulfonyloxy group which may have a halogenatom, a lower alkoxy-substituted lower alkoxycarbonyl group, a loweralkenyl group having halogen atoms and a phenyl-lower alkoxy group, orthe phenyl group having a lower alkylenedioxy group can be exemplifiedby, for example, phenyl groups which may each have, on the phenyl ring,1 to 5 substituents selected from the group consisting of a C₁₋₁₈straight-chain or branched-chain alkoxy group, a silyloxy groupsubstituted with three straight-chain or branched-chain alkyl groupshaving 1 to 6 carbon atoms, a C₁₋₆ straight-chain or branched-chainalkyl group, a hydroxyl group, a C₂₋₆ straight-chain or branched-chainalkenyloxy group, a C₁₋₆ straight-chain or branched-chain alkylthiogroup, a phenyl group, a C₁₋₆ straight-chain or branched-chainalkylsulfonyl group, a C₁₋₆ straight-chain or branched-chainalkylsulfinyl group, a halogen atom, a nitro group, a group of theformula, ##STR29## wherein A represents a C₁₋₆ straight-chain orbranched-chain chain alkylene group or a group of the formula, ##STR30##l represents 0 or 1; R⁸ and R⁹, are each the same or different, and areeach represents a hydrogen atom, a C₁₋₆ straight-chain or branched-chainalkyl group, a C₁₋₆ straight-chain or branched-chain alkanoyl group or aC₁₋₆ straight-chain or branched-chain alkyl group having an amino groupwhich may have, as substituent(s), one to two C₁₋₆ straight-chain orbranched-chain alkyl groups, further R⁸ and R⁹ as well as the adjacentnitrogen atom being bonded thereto, together with or without othernitrogen atom or oxygen atom may form a five- to six-membered saturatedor unsaturated heterocyclic ring. The heterocyclic ring may have a C₁₋₆straight-chain or branched-chain alkanoyl group or a C₁₋₆ straight-chainor branched-chain alkyl group as a substituent!; a C₁₋₆ straight-chainor branched-chain alkanoyl group, a C₁₋₆ straight-chain orbranched-chain alkoxycarbonyl group, a cyano group, atetrahydropyranyloxy group which may have, as substituent(s), 1 to 4groups selected from the group consisting of a hydroxyl group, a C₁₋₆straight-chain or branched-chain alkoxycarbonyl group, a phenylalkoxygroup whose alkoxy moiety is a C₁₋₆ straight-chain or branched-chainphenylalkoxy group, a C₁₋₆ straight-chain or branched-chain alkyl grouphaving one to three hydroxy groups or C₂₋₆ straight-chain orbranched-chain alkanoyloxy groups, and a C₂₋₆ straight-chain orbranched-chain alkanoyloxy group, an amidino group, a hydroxysulfonyloxygroup, a C₁₋₆ straight-chain or branched-chain alkoxycarbonylalkoxygroup whose alkoxy moiety is a C₁₋₆ straight-chain or branched-chainalkoxy group, a carboxyalkoxy group whose alkoxy moiety is a C₁₋₆straight-chain or branched-chain alkoxy group, a mercapto group, aalkoxyalkoxy group whose alkoxy moiety is a C₁₋₆ straight-chain orbranched-chain alkoxy group, a C₁₋₆ straight-chain or branched-chainalkyl group having 1 to 3 hydroxyl groups, a C₂₋₆ straight-chain orbranched-alkenyl group, a thiocarbonyloxy group having an amino groupwhich may have one to two C₁₋₆ straight-chain or branched-chain alkylgroups as substituent(s), a carbonylthio group having an amino groupwhich may have one to two C₁₋₆ straight-chain or branched-chain alkylgroups as substituent(s), a C₁₋₆ straight-chain or branched-chain alkylgroup having one to three C₁₋₆ straight-chain or branched-chain alkanoylgroup, a carboxy group, a group of the formula, ##STR31## (R²¹ and R²²,are each the same or different, and are each represents a hydrogen atomor a C₁₋₆ straight-chain or branched-chain alkyl group), a phenylalkoxygroup whose alkoxy moiety is a C₁₋₆ straight-chain or branched-chainalkoxy group, a C₂₋₆ straight-chain or branched-chain alkynyl group, analkoxycarbonylalkyl group having a C₁₋₆ straight-chain or branched-chainalkoxy moiety and a C₁₋₆ straight-chain or branched-chain alkyl moiety,a carboxyalkyl group whose alkyl moiety is a C₁₋₆ straight-chain orbranched-chain alkyl group, an alkoxycarbonylalkenyl group having a C₁₋₆straight-chain or branched-chain alkoxy moiety and a C₂₋₆ straight-chainor branched-chain alkenyl moiety, a carboxyalkenyl group whose alkenylmoiety is a C₂₋₆ straight-chain or branched-chain alkenyl group, a C₁₋₆straight-chain or branched-chain alkylsulfonyloxy group which may have 1to 3 halogen atoms, an alkoxyalkoxycarbonyl group whose alkoxy moiety isa C₁₋₆ straight-chain or branched-chain alkoxy group, a C₂₋₆straight-chain or branched-chain alkenyl group having 1 to 3 halogenatoms, and a phenylalkoxy group having a C₁₋₆ straight-chain orbranched-chain alkoxy moiety, or phenyl groups each having a C₁₋₄straight-chain or branched-chain alkylenedioxy group, such as phenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl,3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl,4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl,3-ethoxy-4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-diethoxyphenyl,3,5-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl,3,4,5-trimethoxyphenyl, 3,4-dipentyloxyphenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl,4-ethylphenyl, 3-butylphenyl, 4-isopropylphenyl, 4-pentylphenyl,4-hexylphenyl, 3,4-dimethylphenyl, 3,4-diethylphenyl,2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4,5-trimethylphenyl,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl,3,5-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,4-dihydroxyphenyl,2,6-dihydroxyphenyl, 3,4,5-trihydroxyphenyl, 2-methylthiophenyl,3-methylthiophenyl, 4-methylthiophenyl, 2-ethylthiophenyl,3-ethylthiophenyl, 4-ethylthiophenyl, 4-isopropylthiophenyl,4-pentylthiophenyl, 4-hexylthiophenyl, 3,4-dimethylthiophenyl,3,4-diethylthiophenyl, 2,5-dimethylthiophenyl, 2,6-dimethylthiophenyl,3,4,5-trimethylthiophenyl, 2-phenylphenyl, 3-phenylphenyl,4-phenylphenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl,4-methylsulfonylphenyl, 2-ethylsulfonylphenyl,4-isopropylsulfonylphenyl, 4-pentylsulfonylphenyl,4-hexylsulfonylphenyl, 3,4-dimethylsulfonylphenyl,3,4-diethylsulfonylphenyl, 2,5-dimethylsulfonylphenyl,2,6-dimethylsulfonylphenyl, 3,4,5-trimethylsulfonylphenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl,4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl,2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl,3,5-dibromophenyl, 3,4,5-trichlorophenyl, 2,3,4,5,6-pentafluorophenyl,2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3,4-dinitrophenyl,2,5-dinitrophenyl, 2,6-dinitrophenyl, 3,4,5-trinitrophenyl,2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-methylaminophenyl,3-ethylaminophenyl, 4-propylaminophenyl, 2-isopropylaminophenyl,3-butylaminophenyl, 4-pentylaminophenyl, 2-hexylaminophenyl,4-dimethylaminophenyl, 3-(N-methyl-N-ethylamino)phenyl,3-dihexylaminophenyl, 2-(N-methyl-N-acetylamino)phenyl,4-(N-acetylamino)phenyl, 3-(N-acetylamino)phenyl,4-(N-formylamino)phenyl, 4-(N-isobutyrylamino)phenyl,2-(N-pentanoylamino)phenyl, 3,4-di(N-acetylamino)phenyl,3,4-diaminophenyl, 3,4,5-triaminophenyl, 2,6-diaminophenyl,2,5-diaminophenyl, 2-carbamoylphenyl, 3-carbamoylphenyl,4-carbamoylphenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl,2-formylphenyl, 3-propionylphenyl, 4-isobutyrylphenyl,2-pentanoylphenyl, 3-hexanoylphenyl, 3,4-diacetylphenyl,2,5-diacetylphenyl, 3,4,5-triacetylphenyl, 2-methoxycarbonylphenyl,2-ethoxycarbonylphenyl, 3-ethoxycarbonylphenyl, 4-ethoxycarbonylphenyl,3-propoxycarbonylphenyl, 4-butoxycarbonylphenyl,4-pentyloxycarbonylphenyl, 4-hexyloxycarbonylphenyl,3,4-diethoxycarbonylphenyl, 2,5-diethoxycarbonylphenyl,2,6-diethoxycarbonylphenyl, 3,4,5-triethoxycarbonylphenyl,2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 3,4-dicarboxyphenyl,2,5-dicarboxyphenyl, 2,6-dicarboxyphenyl, 3,4,5-tricarboxyphenyl,3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl,2,3-trimethylenedioxyphenyl, 3,4-tetramethylenedioxyphenyl,3,5-di-tert-butyl-4-hydroxyphenyl, 3-hydroxy-4-pentyloxyphenyl,2-hydroxy-5-tert-butylphenyl, 3,5-dichloro-4-aminophenyl,3-(N-acetylamino)-4-hydroxyphenyl, 3-amino-4-hydroxyphenyl,3-(N-methyl-N-acetylamino)-4-methoxyphenyl,3-nitro-4-(N-acetylamino)phenyl, 3-nitro-4-chlorophenyl,3-chloro-4-methylphenyl, 3-methoxy-4-hydroxyphenyl,3-hydroxy-4-methoxyphenyl, 3-methoxy-4-hydroxy-5-iodophenyl,3,4-dimethoxy-5-bromophenyl, 3,5-diiodo-4-hydroxyphenyl,4-(dimethyl-tert-butylsilyloxy)phenyl, 3-(tri-tert-butylsilyloxy)phenyl,2-(trimethylsilyloxy)phenyl,3-amino-4-(dimethyl-tert-butylsilyloxy)phenyl, 4-allyloxyphenyl,2-vinyloxyphenyl, 3-(2-butenyloxy)phenyl, 2-(3-butenyloxy)phenyl,3-(1-methylallyloxy)phenyl, 4-(2-pentenyloxy)phenyl,2-(2-hexenyloxy)phenyl, 3-methyl-4-allyloxyphenyl,3-methoxy-4-octadecyloxyphenyl, 4-dimethylamidophenyl,2-methylamidophenyl, 3-ethylamidophenyl, 4-propylamidophenyl,2-isopropylamidophenyl, 3-butylamidophenyl, 4-pentylamidophenyl,2-hexylamidophenyl, 3-diethylamidophenyl,4-(N-methyl-N-propylamido)phenyl, 2-methylsulfinylphenyl,3-methylsulfinylphenyl, 4-methylsulfinylphenyl, 2-ethylsulfinylphenyl,3-ethylsulfinylphenyl, 4-ethylsulfinylphenyl, 4-isopropylsulfinylphenyl,4-pentylsulfinylphenyl, 4-hexylsulfinylphenyl,3,4-dimethylsulfinylphenyl, 3,4-diethylsulfinylphenyl,2,5-dimethylsulfinylphenyl, 2,6-dimethylsulfinylphenyl,3,4,5-trimethylsulfinylphenyl, 3-methoxy-4-methylsulfinylphenyl,2-acetyloxyphenyl, 3-acetyloxyphenyl, 4-acetyloxyphenyl,2-formyloxyphenyl, 3-propionyloxyphenyl, 4-isobutyryloxyphenyl,2-pentanoyloxyphenyl, 3-hexanoyloxyphenyl, 3,4-diacetyloxyphenyl,2,5-diacetyloxyphenyl, 3,4,5-triacetyloxyphenyl,3,5-bis(acetylamino)phenyl, 2-amidinophenyl, 4-amidinophenyl,3-amidinophenyl, 4-(4-methyl-1-piperazinyl)-3-nitriophenyl,4-hydroxysulfonyloxyphenyl, 3-hydroxysulfonyloxyphenyl,2-hydroxysulfonyloxyphenyl, 4-hydroxy-3-acetylaminophenyl,4-(2,3,4,6-tetra-o-acetyl-β-D-glucopyranosyloxy)phenyl,4-(β-D-glucopyranosyloxy)phenyl,4-(2,3,4,6-tetra-o-benzyl-β-D-glucopyranosyloxy)phenyl,3,5-bis(dimethylamino)phenyl, 4-chloro-3-nitrophenyl,4-(4-methyl-1-piperazinyl)-3-nitrophenyl, 4-cyanophenyl,3-acetylamino-4-(methyl-1-piperazinyl)phenyl,3-nitro-4-morpholinophenyl, 4-(1-piperazinyl)-3-nitrophenyl,4-(1-piperazinyl)-3-nitrophenyl, 4-hydroxy-3-carboxyphenyl,4-morpholino-3-aminophenyl, 4-hydroxy-3-aminophenyl,4-hydroxy-3-(2-dimethylaminoethylamino)phenyl,4-methoxy-3-(4-acetyl-1-piperazinyl)phenyl,4-methoxy-3-(1-piperazinyl)phenyl,4-methoxy-3-(4-methyl-1-piperazinyl)phenyl,4-methoxy-3-(4-ethyl-1-piperazinyl)phenyl, 4-hydroxy-3-aminophenyl,4-hydroxy-3- (4-methyl-1-piperazinyl)methyl!phenyl, 4-methoxy-3-(1-pyrrolidinyl)methyl!phenyl, 3,5-diacetyloxyphenyl,3-methoxy-5-methoxycarbonylphenyl, 3-methoxy-5-carboxyphenyl,3-methoxy-5- (4-methyl-1-piperazinyl)carbonyl!phenyl, 3-methoxy-5-(1-pyrrolidinyl)-carbonyl!phenyl, 3-methoxy-5-(4-methyl-1-piperazinyl)methyl!phenyl, 3-amino-4-carboxyphenyl,3-carbamoyl-4-hydroxyphenyl, 4-hydroxy-3-dimethylamidophenyl,3-methoxycarbonyl-4-methoxycarbonylmethoxyphenyl,4-allyloxy-3-methoxycarbonylphenyl, 3-carboxy-4-carboxymethoxyphenyl,4-hydroxy-4-allyl-3-methoxycarbonylphenyl, 3-carboxy-4-allyloxyphenyl,4-hydroxy-3-carboxy-5-allylphenyl, 4-mercapto-3-carboxyphenyl,5-nitro-4-hydroxy-3-methoxycarbonylphenyl,5-nitro-3-methoxycarbonylphenyl,3-methoxycarbonyl-4-methoxymethoxyphenyl,3-methoxycarbonyl-5-aminophenyl, 3-carboxy-5-aminophenyl,5-methoxycarbonyl-3-bromo-2-aminophenyl, 2-cyanophenyl, 4-cyanophenyl,3-cyanophenyl, 3-methoxycarbonyl-4-hydroxyphenyl,3-carboxy-4-hydroxy-5-(1,1-dimethyl-2-propenyl)phenyl,2-hydroxy-3-carboxyphenyl, 3-carboxy-4-hydroxy-5-(2-isopropenyl)phenyl,3-carboxy-4-hydroxy-5-methylphenyl, 3-methoxycarbonyl-4-methoxyphenyl,3-methoxycarbonyl-4-hydroxy-5-aminophenyl,3-carboxy-4-hydroxy-5-propylphenyl, 3-carboxy-4-hydroxy-5-aminophenyl,3-carboxy-4-hydroxy-5-chlorophenyl, 3-carboxy-6-hydroxyphenyl,4-ethoxyphenyl, 3,4-dibutoxyphenyl, 3,4-dipropoxyphenyl,3-methoxy-4-ethoxyphenyl, 3-propoxy-4-methoxyphenyl,3-ethoxy-4-methoxyphenyl, 3,4-didecyloxyphenyl, 2,4-diethoxyphenyl,3-ethoxy-4-propoxyphenyl, 3-carboxy-4-hydroxy-5-isobutylphenyl,3-carboxy-4-acetylaminophenyl,3-carboxy-4-hydroxy-5-(2-hydroxyethyl)phenyl,3-carboxy-4-amino-6-hydroxyphenyl,3-carboxy-4-hydroxy-5-(2,3-dihydroxypropyl)phenyl,3-carboxy-4-aminophenyl, 3-carboxy-4-acetyloxyphenyl,3-ethyl-4-hydroxyphenyl, 3-carboxy-5-hydroxyphenyl,4-carboxy-3,5-dihydroxyphenyl, 3-carboxy-4,6-dihydroxyphenyl,5-methoxycarbonyl-3-amino-2-hydroxyphenyl,2-allyloxy-5-methoxycarbonylphenyl, 3-carboxy-6-methoxyphenyl,3-methoxycarbonyl-6-hydroxyphenyl, 3-carbonyl-6-allyloxyphenyl,3-carboxy-5-nitro-6-hydroxyphenyl, 3-carboxy-5-allyl-6-hydroxyphenyl,3-carboxy-6-hydroxyphenyl, 3-carboxy-5-amino-6-hydroxyphenyl,3-methoxycarbonyl-4-dimethylaminothiocarbonyloxyphenyl,3-methoxycarbonyl-4-dimethylaminocarbonylthiophenyl,3-methoxycarbonyl-4-hydroxy-5-(2,3-dihydroxypropyl)phenyl,3-methoxycarbonyl-4-hydroxy-5-formylmethylphenyl,3-methoxycarbonyl-4-hydroxy-5-(2-hydroxyethyl)phenyl,3-ethoxycarbonyl-4-acetylaminophenyl, 3-methoxycarbonyl-5-hydroxyphenyl,3-methoxycarbonyl-4-acetylamino-6-hydroxyphenyl,3-methoxycarbonyl-6-methoxyphenyl, 4-propoxy-3-ethoxyphenyl,3-methoxycarbonyl-5-allyl-6-hydroxyphenyl,3-methoxycarbonyl-4-(2-butenyloxy)phenyl,3-methoxycarbonyl-4-hydroxy-5-(1-methyl-2-propenyl)phenyl,3-methoxycarbonyl-4-(2-isopentenyloxy)phenyl,3-methoxycarbonyl-4-hydroxy-5-(1,1-dimethyl-2-propenyl)phenyl,3-methoxycarbonyl-4-(2-methyl-2-propenyloxy)phenyl,3-methoxycarbonyl-4-hydroxy-5-(2-methyl-2-propenyl)phenyl,5-chloro-4-hydroxy-3-methoxycarbonylphenyl,3-methoxycarbonyl-4-hydroxy-5-methylphenyl, 3,5-dinitro-4-hydroxyphenyl,4-hydroxy-3-nonyloxycarbonylphenyl, 4-hydroxy-3-benzyloxycarbonylphenyl,4-hydroxy-3-(2-methyl-2-propenyl)-5-benzyloxycarbonyl,4-hydroxy-3-(2-methyl-2-propenyl)-5-nonyloxycarbonylphenyl, ##STR32## 4-2-(1-piperidinyl)ethylamino!-3-carboxyphenyl, 4-methoxy-3-carboxyphenyl,2-methyl-4-hydroxy-5-carboxyphenyl, 3-ethyl-4-hydroxy-3-carboxyphenyl,3-(4-ethyl-1-piperazinyl)-4-hydroxyphenyl,4-(2-hydroxy-3-carboxyphenyl)phenyl, 4-2-(3,4-diethoxyphenyl)-4-thiazolyl!-3-hydroxy-2-carboxyphenyl,4-hydroxy-3-hydroxymethylphenyl, 4-ethoxy-3-carboxyphenyl,4-n-butoxy-3-n-butoxycarbonylphenyl, 4-n-butoxy-3-carboxyphenyl,3-acetylmethyl-4-hydroxy-3-carboxyphenyl,3-n-butyl-4-hydroxy-3-carboxyphenyl, 3-allyl-4-hydroxy-3-carboxyphenyl,3-hydroxymethyl-4-hydroxy-3-carboxyphenyl,3-formyl-4-hydroxy-5-carboxyphenyl,5-(2-carboxyethyl)-4-hydroxy-3-carboxyphenyl,5-(2-methoxycarboxyethyl)-4-hydroxy-3-carboxyphenyl,5-methylaminomethyl-4-hydroxy-3-carboxyphenyl,5-(2-carboxyvinyl)-4-hydroxy-3-carboxyphenyl,5-(2-methoxycarboxyvinyl)-4-hydroxy-3-carboxyphenyl,5-acetyl-4-hydroxy-3-carboxyphenyl, 5-phenyl-4-hydroxy-3-carboxyphenyl,5-bromo-4-hydroxy-3-carboxyphenyl, 5-cyano-4-hydroxy-3-carboxyphenyl,4,5-hydroxy-3-carboxyphenyl, 5-methoxy-4-hydroxy-3-carboxyphenyl,5-ethylamino-4-hydroxy-3-carboxyphenyl,5-acetylamino-4-hydroxy-3-carboxyphenyl, 3,5-dicarboxy-4-hydroxyphenyl,4-methoxy-3-carboxyphenyl, 4-ethoxy-3-carboxyphenyl,4-n-butyoxy-3-carboxyphenyl, 4-dimethylamino-3-hydroxyphenyl,4-dimethylamino-3-hydroxymethylphenyl,4-dimethylamino-3-methoxycarboxyphenyl,4-trifluoromethylsulfonyloxy-3-methoxycarbonylphenyl,3-methoxymethoxycarbonyl-4-methoxymethoxy-5-(1-propenyl)phenyl,3-methoxymethoxycarbonyl-4-methoxymethoxy-5-formylphenyl,3-methoxymethoxycarbonyl-4-methoxymethoxy-5-acetylmethylphenyl,5-(2-methyl-2-propenyl)-4-methoxymethoxy-3-methoxymethoxycarbonylphenyland the like.

The 5- to 15-membered monocylic, bicyclic or tricyclic heterocyclicresidual group having i to 2 hetero atoms selected from the groupconsisting of a nitrogen atom, an oxygen atom and a sulfur atom can beexemplified by pyrrolidinyl, piperidinyl, pierazinyl, morpholino,pyridyl, 1,2,5,6-tetrahydropyridylthienyl, quinolyl,1,4-dihydroquinolyl, benzothiazolyl, pyrazyl, pyrimidyl,pyridazylthienyl, pyrrolyl, carbostyril, 3,4-dihydrocarbostyril,1,2,3,4-tetrahydroquinolyl, indolyl, isoindolyl, indolinyl,benzoimidazolyl, benzoxazolyl, imidazolidinyl, isoquinolyl,quinazolidinyl, quinoxalinyl, cinnolinyl, phthalazinyl, carbazolyl,acrydinyl, chromanyl, isoindolinyl, isochromanyl, pyrazolyl, imidazolyl,pyrazolidinyl, phenothiazinyl, benzofuryl, 2,3-dihydrobenzo b!furyl,benzothienyl, phenoxthinyl, phenoxazinyl, 4H-chromenyl, 1H-indazolyl,phenazinyl, xanthenyl, thianthrenyl, isoindolinyl, 2-imidazolinyl,2-pyrrolinyl, furyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl,pyranyl, pyrazolidinyl, 2-pyrazolinyl, quinuclidinyl, 1,4-benzoxazinyl,3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzothiazinyl,1,4-benzothiazinyl, 1,2,3,4-tetrahydroquinoxalinyl,1,3-dithia-2,4-dihydronaphthalenyl, phenanthridinyl,1,4-dithianaphthalenyl, dibenzo b,e!azepine and 6,11-dihydro-5H-dibenzob,e!azepine.

The heterocyclic ring having 1 to 3 groups selected from the groupconsisting of an oxo group, an alkyl group, a benzoyl group, a loweralkanoyl group, a hydroxyl group, a carboxy group, a loweralkoxycarbonyl group, a lower alkylthio group, a group ##STR33## (A andl are the same as defined above; R²³ and R²⁴ are each the same ordifferent, and are each represents a hydrogen atom or a lower alkylgroup; further R²³ and R²⁴ as well as the adjacent nitrogen atom beingbonded thereto, together with or without other nitrogen atom or oxygenatom may form a five- to six-membered saturated heterocyclic group; saidfive- to six-membered heterocyclic group may have a lower alkyl group asa substituent.), a cyano group, a lower alkyl group having hydroxylgroups, a phenylaminothiocarbonyl group and an amino-loweralkoxycarbonyl group which may have lower alkyl groups as substituents,can be exemplified by heterocyclic rings each having 1 to 3 groupsselected from the group consisting of an oxo group, a C₁₋₁₈straight-chain or branched-chain alkyl group, a benzoyl group, a C₁₋₆straight-chain or branched-chain alkanoyl group, a hydroxyl group, acarboxy group, a C₁₋₆ straight-chain or branched-chain alkoxycarbonylgroup, a C₁₋₆ straight-chain or branched-chain alkylthio group, a groupof the formula, ##STR34## (A is the same as defined above; R²³ and R²⁴,are each the same or different, and are each represent a hydrogen atomor a C₁₋₆ straight-chain or branched-chain alkyl group, further R²³ andR²⁴ as well as the adjacent nitrogen atom being bonded thereto, togetherwith or without other nitrogen atom or oxygen atom may form a five- tosix-membered saturated heterocyclic ring, said heterocyclic ring mayhave a C₁₋₆ straight-chain or branched-chain alkyl group as asubstituent.), a cyano group, a C₁₋₆ straight-chain or branched-chainalkyl group having 1 to 3 hydroxyl groups, a phenylaminothiocarbonylgroup and a C₁₋₆ straight-chain or branched-chain alkoxycarbonyl grouphaving an amino group which may have one to two C₁₋₆ straight-chain orbranched-chain alkyl groups as substituent(s), such as dibenzob,e!-azepin-3-yl-6-one, 4-oxo-1,4-dihydroquinolyl, 1-oxopyridyl,2-oxo-pyridyl, 1-methyl-3,4-dihydrocarbostyril, 1-ethylcarbostyril,1-butyl-3,4-dihydrocarbostyril, 1-hexylcarbostyril,1-octadecyl-3,4-dihydrocarbostyril,3-oxo-4-methyl-3,4-dihydro-2H-1,4-benzothiazinyl,3-oxo-3,4-dihydro-2H-1,4-benzothiazinyl,1-benzoyl-1,2,3,4-tetrahydroquinolyl,1-octadecyl-1,2,3,4-tetrahydroquinolyl, 1-benzoylcarbostyril,4-benzoyl-3,4-dihydro-2H-1,4-benzothiazolyl,4-methyl-1,2,3,4-tetrahydroquinoxalinyl,4-benzoyl-1,2,3,4-tetrahydroquinoxalinyl,1-acetyl-1,2,3,4-tetrahydroquinolyl, 1-acetyl-3,4-dihydrocarbostyril,4-acetyl-3,4-dihydro-2H-1,4-benzothiazolyl,4-benzoyl-3,4-dihydro-2H-1,4-benzoxazinyl,4-acetyl-3,4-dihydro-2H-1,4-benzoxazinyl,4-acetyl-1,2,3,4-tetrahydroquinoxalinyl,1-methyl-1,2,3,4-tetrahydroquinolyl, 7-hydroxy-3,4-dihydrocarbostyril,8-hydroxy-3,4-dihydrocarbostyril, 2-methylthiobenzothiazolyl,3-oxo-3,4-dihydro-2H-1,4-benzoxazinyl, 1-acetylindolinyl,2-oxobenzoimidazolyl, 4-methyl-3,4-dihydro-2H-1,4-benzoxazinyl,10-acetylphenothiazinyl, 2-oxobenzothiazolyl, 2-oxobenzoxazolyl,2-oxo-3-methylbenzothiazolyl, 1,3-dimethyl-2-oxobenzoimidazolyl,6-hydroxy-3,4-dimethylquinolyl, 4-oxopyridyl,1-propyl-1,2,3,4-tetrahydroquinolyl,4-pentyl-1,2,3,4-tetrahydroquinoxalinyl,1-propanoyl-1,2,3,4-tetrahydroquinolyl, 1-butylcarbostyril,4-pentanoyl-3,4-dihydro-2H-1,4-benzothiazolyl,4-hexanoyl-3,4-dihydro-2H-1,4-benzoxazinyl, 2-ethylthiobenzoxazolyl,2-propylthiobenzoimidazolyl, 2-butylthiobenzothiazolyl,6-pentylcarbostyril, 7-hexylthio-3,4-dihydrocarbostyril,2-carboxypyridyl, 2-carboxypyrrolyl, 2-ethoxycarbonylpyridyl,2-methoxycarbonylpyrrolyl, 1-methylpyridinum,1-methyl-1,2,5,6-tetrahydropyridyl, 2-methoxycarbonylfuryl,2-carboxyfuryl, 2-dimethylaminocarbonylpyridyl, 2-acetylpyrrolyl,2-hydroxymethylpyridyl, 2-ethoxycarbonyl-4-methylpyridyl,2-carboxy-4-methylpyridyl, 2-(4-methyl-1-piperazinyl)carboxypyridyl,2-(2-dimethylaminoethoxycarbonyl)pyridyl, 2-dimethylaminomethylpyridyl,2-ethoxycarbonylthienyl, 2-methyl-7-carboxybenzofuryl, 2-carboxythienyl,4-ethoxycarbonylthiazolyl, 4-carboxythiazolyl,4-methyl-5-carboxythiazolyl, 3-carboxypyridyl,2,2-dimethyl-7-carboxy-2,3-dihydrobenzo b!furyl, 4-carboxypyridyl,2-methyl-4-carbamoylpyridyl, 2,6-dimethyl-3-carbamoylpyridyl,2-phenylaminothiocarbonylpyridyl, 2-methyl-3-carboxypyridyl,2,6-dimethyl-3-carboxypyridyl and the like.

As to the lower alkenyloxy group, there can be mentioned C₂₋₆straight-chain or branched-chain alkenyloxy groups such as vinyloxy,allyloxy, 2-butenyloxy, 3-butenyloxy, 1-methylallyloxy, 2-pentenyloxy,2-hexenyloxy and the like.

The lower alkylsulfinyl group can be exemplifed by C₁₋₆ straight-chainor branched-chain alkylsulfinyl groups such as methylsulfinyl,ethylsulfinyl, isopropylsulfinyl, butylsulfinyl, tert-butylsulfinyl,pentylsulfinyl, hexylsulfinyl and the like.

As to the lower alkanoyloxy group, there can be mentioned C₁₋₆straight-chain or branched-chain alkanoyloxy groups such as formyloxy,acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy,tert-butylcarbonyloxy, hexanoyloxy and the like.

The tri-lower alkyl group-substituted silyloxy group can be exemplifiedby silyloxy groups each substituted with three C₁₋₆ straight-chain orbranched-chain alkyl groups, such as trimethylsilyloxy,triethylsilyloxy, triisopropylsilyloxy, tributylsilyloxy,tri-tert-butylsilyloxy, tripentylsilyloxy, trihexylsilyloxy,dimethyl-tert-butylsilyloxy and the like.

The phenyl-lower alkyl group which may have a lower alkoxy group as asubstituent on the phenyl ring and a hydroxyl group as a substituent onthe lower alkyl group, can be exemplified by phenylalkyl groups eachhaving a C₁₋₆ straight-chain or branched-chain alkyl group moiety, whichmay each have one to three C₁₋₆ straight chain or branched chain alkoxygroups as substituent(s) on the phenyl ring and a hydroxyl group as asubstituent on the lower alkyl group, such as benzyl, 2-phenylethyl,1-phenylethyl, 3-phenylpropyl, 4-pehnylbutyl,1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl,2-methyl-3-phenylpropyl, 2-methoxybenzyl, 2-(3-methoxyphenyl)ethyl,1-(4-methoxyphenyl)ethyl, 3-(2-ethoxyphenyl)propyl,4-(3-ethoxyphenyl)butyl, 1,1-dimethyl-2-(4-isopropoxyphenyl)ethyl,5-(4-pentyloxyphenyl)pentyl, 6-(4-hexyloxyphenyl)hexyl,3,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl,3,4,5-trimethoxybenzyl, 1-phenyl-1-hydroxymethyl,2-phenyl-1-hydroxyethyl, 1-phenyl-2-hydroxyethyl,3-phenyl-1-hydroxypropyl, 4-phenyl-4-hydroxybutyl,5-phenyl-5-hydroxypentyl, 6-phenyl-6-hydroxyhexyl,2-methyl-3-phenyl-3-hydroxypropyl, 1-(2-methoxyphenyl)-1-hydroxymethyl,2-(3-methoxyphenyl)-1-hydroxyethyl, 3-(2-ethoxyphenyl)-2-hydroxypropyl,4-(3-ethoxyphenyl)-3-hydroxybutyl,5-(4-pentyloxyphenyl)-4-hydroxypentyl,6-(4-hexyloxyphenyl)-5-hydroxyhexyl, 6-(4-hexyloxyphenyl)-1-hydroxhexyl,1-(3,4-dimethoxyphenyl)-1-hydroxymethyl,1-(3,4,5-trimethoxyphenyl)-1-hydroxymethyl and the like.

The benzoyl group which may have lower alkoxy groups as substituents onthe phenyl ring, can be exemplified by benzoyl groups which may eachhave one to three C₁₋₆ straight-chain or branched-chain alkoxy groups assubstituent(s) on the phenyl ring, such as benzoyl, 2-methoxybenzoyl,3-methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoyl,4-isopropoxybenzoyl, 4-pentyloxybenzoyl, 4-hexyloxybenzoyl,3,4-dimethoxybenzoyl, 3-ethoxy-4-methoxybenzoyl, 2,3-dimethoxybenzoyl,3,4-diethoxybenzoyl, 2,5-dimethoxybenzoyl, 2,6-dimethoxybenzoyl,3,5-dimethoxybenzoyl, 3,4-dipentyloxybenzoyl, 3,4,5-trimethoxybenzoyland the like.

The phenyl-lower alkenyl group which may have lower alkoxy groups assubstituents on the phenyl group, can be exemplified by phenylalkenylgroups each having a C₃₋₆ straight chain or branched chain alkenylmoiety, which may each have one to three C₁₋₆ straight chain or branchedchain alkoxy groups as substituents on the phenyl ring, such ascinnamyl, styryl, 4-phenyl-3-butenyl, 4-phenyl-2-butenyl,5-phenyl-4-pentenyl, 5-phenyl-3-pentenyl, 5-phenyl-2-pentenyl,6-phenyl-5-hexenyl, 6-phenyl-4-hexenyl, 6-phenyl-3-hexenyl,6-phenyl-2-hexenyl, 2-methyl-4-phenyl-3-butenyl, 2-methylcinnamyl,1-methylcinnamyl, 2-methoxystyryl, 3-methoxycinnamyl, 4-methoxystyryl,2-ethoxycinnamyl, 3-ethoxystyryl, 4-ethoxystyryl, 2-propoxystyryl,3-propoxystyryl, 4-propoxycinnamyl, 3-(tert-butoxy)styryl,4-pentyloxycinnamyl, 3-hexyloxystyryl, 3,4-dimethoxystyryl,3,5-dimethoxystyryl, 2,6-dimethoxystyryl, 3,4-diethoxystyryl,3,5-diethoxystyryl, 3,4,5-trimethoxystyryl, 4-ethoxyphenyl-3-butenyl,4-(3-tertbutoxyphenyl)-2-butenyl, 5-(4-hexyloxyphenyl)-4-pentenyl,6,(3,4-dimethoxyphenyl)-5-hexenyl, 6-(3,4,5-triethoxyphenyl)-3-hexenyland the like.

The amino-lower alkyl group which may have lower alkyl groups assubstituents, can be exemplified by amino group-containing C₁₋₆straight-chain or branched-chain alkyl groups which may each have one totwo C₁₋₆ straight-chain or branched-chain alkyl groups assubstituent(s), such as aminomethyl, 2-eminoethyl, 1-aminoethyl,3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl,1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl,1-ethylaminoethyl, 2-propylaminoethyl, 3-isopropylaminopropyl,4-butylaminobutyl, 5-pentylaminopentyl, 6-hexylaminohexyl,dimethylaminomethyl, (N-ethyl-N-propylamino)methyl,2-(N-methyl-N-hexylamino)ethyl and the like.

The five- or six-membered saturated or unsaturated heterocyclic ringwhich R^(s) and R⁹ as well as the adjacent nitrogen atom bonded theretomay form together with or without other nitrogen atom or oxygen atom,can be exemplified by piperazinyl, pyrrolidinyl, morpholinyl,piperidinyl, pyrrolyl, imidazolyl, pyrazolyl, 2-pyrrolinyl,2-imidazolinyl, imidazolidinyl, 2-piperazolinyl, pyrazolidinyl,1,2,5,6-tetrahydropyridyl, etc.

The above heterocyclic ring substituted with a lower alkanoyl group or alower alkyl group can be exemplified by above heterocyclic rings eachsubstituted with a C₁₋₅ straight-chain or branched-chain alkanoyl groupor a C₁₋₆ straight-chain or branched-chain alkyl group, such as4-acetylpiperazinyl, 3-formylpyrrolidinyl, 2-propionylpyrrolidinyl,4-butyrylpiperidinyl, 3-pentanoylpiperazinyl, 2-hexanoylmorpholino,4-methylpiperazinyl, 4-ethylpiprazinyl, 3-ethylpyrrolidinyl,2-propylpyrrolidinyl, 4-butylpiperidinyl, 3-pentylmorpholino,2-hexylpiprazinyl, 2-acetylpyrrolyl and the like.

The phenyl-lower alkoxy group can be exemplified by phenylalkoxy groupseach having a C₁₋₆ straight-chain or branched-chain alkoxy moiety, suchas benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy,4-phenylbutoxy, 1,1-dimethyl-2-phenylethoxy, 5-phenylpentyloxy,6-phenylhexyloxy, 2-methyl-3-phenylpropoxy and the like.

As to the hydroxyl group- or lower alkanoyloxy group-substituted loweralkyl group, there can be mentioned C₁₋₆ straight-chain orbranched-chain alkyl groups each having one to three hydroxyl groups orone to three C₁₋₆ straight-chain or branched-chain alkanoyloxy groups,such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl,2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl,5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl,1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl, acetyloxymethyl,2-propionyloxyethyl, 1-butyryloxyethyl, 3-acetyloxypropyl,2,3-diacetyloxypropyl, 4-isobutyryloxybutyl, 5-pentanoyloxypentyl,6-tert-butylcarbonyloxyhexyl, 1,1-dimethyl-2-hexanoyloxyethyl,5,5,4-triacetyloxypentyl, 2-methyl-3-acetyloxypropyl and the like.

The tetrahydropyranyloxy group which may have, as substituent(s), one tofour groups selected from the group consisting of a hydroxyl group, alower alkoxycarbonyl group, a phenyl-lower alkoxy group, a hydroxylgroup- or lower alkanoyloxy group-substituted lower alkyl group and alower alkanoyloxy group, can be exemplified by tetrahydropyranyloxygroups which may each have, as substituent(s), one to four groupsselected from the group consisting of a hydroxyl group, a C₁₋₆straight-chain or branched-chain alkoxycarbonyl group, a phenylalkoxygroup having a C₁₋₆ straight-chain or branched-chain alkoxy moiety, aC₁₋₆ straight-chain or branched-chain alkyl group having one to threehydroxyl groups or one to three C₁₋₆ straight-chain or branched-chainalkanoyloxy groups, and a C₂₋₆ straight-chain or branched-chainalkanoyloxy group, such as 2-, 3- or 4-tetrahydropyranyloxy,3,4,5-trihydroxy-6-methoxycarbonyl-2-tetrahydropyranyloxy,3,4,5-tribenzyloxy-6-hydroxymethyl-2-tetrahydropyranyloxy,3,4,5-triacetyloxy-6-acetyloxymethyl-2-tetrahydropyranyloxy,3,4,5-trihydroxy-6-hydroxymethyl-2-tetrahydropyranyloxy,3-hydroxy-2-tetrahydropyranyloxy, 2,4-dihydroxy-3-tetrahydropyranyloxy,2,3,5-trihydroxy-4-tetrahydropyranyloxy,3-(2,3-dihydroxypropyl)-2-tetrahydropyranyloxy,6-methoxycarbonyl-2-tetrahydropyranyloxy,6-(5,5,4-trihydroxypentyl)-2-tetrahydropyranyloxy,4-carbonyl-4-tetrahydropyranyloxy,4,5,6-trimethoxycarbonyl-2-tetrahydropyranyloxy,2-propoxycarbonyl-3-tetrahydropyranyloxy,6-butoxycarbonyl-4-tetrahydryopyranyloxy,6-pentyloxycarbonyl-2-tetrahydropyranyloxy,4-hexyloxycarbonyl-3-tetrahydropyranyloxy,3,4,5,6-tetrahydroxy-2-tetrahydropyranyloxy,6-benzyloxy-2-tetrahydropyranyloxy,4-(2-phenylethoxy)-3-tetrahydropyranyloxy,4,6-dibenzyloxy-4-tetrahydropyranyloxy,4,5,6-tribenzyloxy-2-tetrahydropyranyloxy,2-(3-phenylpropoxy)-3-tetrahydropyranyloxy,6-(4-phenylbutoxy)-4-tetrahydropyranyloxy,6-(5-phenylpentyloxy)-2-tetrahydropyranyloxy,4-(6-phenylhexyloxy)-3-tetrahydropyranyloxy,3,4,5-trihydroxy-6-benzyloxy-2-tetrahydropyranyloxy,6-acetyloxy-2-tetrahydropyranyloxy,4-propionyloxy-3-tetrahydropyranyloxy,4,6-diacetyloxy-4-tetrahydropyranyloxy,4,5,6-triacetyloxy-2-tetrahydropyranyloxy,2-butyryloxy-3-tetrahydropyranyloxy,6-pentanoyloxy-3-tetrahydropyranyloxy,4-hexanoyloxy-3-tetrahydropyranyloxy,3,4,5-trihydroxy-6-acetyloxy-2-tetrahydropyranyloxy,6-hydroxymethyl-2-tetrahydropyranyloxy,4-(2-hydroxyethyl)-2-tetrahydropyranyloxy,4,6-dihydroxymethyl-4-tetrahydropyranyloxy,4,5,6-dihydroxymethyl-2-tetrahydropyranyloxy,2-(3-hydroxypropyl)-3-tetrahydropyranyloxy,6-acetyloxyethyl-2-tetrahydropyranyloxy,4-(2-acetyloxyethyl)-2-tetrahydropyranyloxy,4,6-diacetyloxymethyl-4-tetrahydropyranyloxy,4,5,6-triacetyloxymethyl-2-tetrahydropyranyloxy,2-(3-propionyloxypropyl)-3-tetrahydropyranyloxy,6-(4-butyryloxybutyl)-4-tetrahydropyranyloxy,6-(5-hydroxypentyl)-2-tetrahydropyranyloxy,4-(6-hexanoyloxyhexyl)-3-tetrahydropyranyloxy,3,4,5-trihydroxymethyl-6-acetyloxymethyltetrahydropyranyloxy and thelike.

The piperazinyl-lower alkyl group which may have lower alkyl groups assubstituents on the piperazine ring, can be exemplified bypiperazinylalkyl groups each having a C₁₋₆ straight-chain orbranched-cahin lower alkyl moiety, which may each have one to three C₁₋₆straight-chain or branched-chain alkyl groups as substituent(s) on thepiperazine ring, such as (1-piperazinyl)methyl, 2-(1-piperazinyl)ethyl,1-(1-piperazinyl)ethyl, 3-(1-piperazinyl)propyl, 4-(1-piperazinyl)butyl,5-(1-piperazinyl)pentyl, 6-(1-piperazinyl)hexyl,1,1-dimethyl-2-(1-piperazinyl)ethyl, 2-methyl-3-(1-piperazinyl)propyl,(4-methyl-1-piperazinyl)methyl, 2-(4-ethyl-1-piperazinyl)ethyl,1-(4-propyl-1-piperazinyl)ethyl, 3-(4-butyl-1-piperazinyl)propyl,4-(4-pentyl-1-piperazinyl)butyl, 5-(4-hexyl-1-piperazinyl)pentyl,6-(3,4-dimethyl-1-piperazinyl)hexyl,1,1-dimethyl-(3,4,5-trimethyl-1-piperazinyl)ethyl and the like.

As to the lower alkoxycarbonyl-substituted lower alkoxy group, there canbe mentioned C₁₋₆ straight-chain or branched-chain alkoxycarbonylalkoxygroups each having a C₁₋₆ straight-chain or branched-chain alkoxymoiety, such as methoxycarbonylmethoxy, 3-methoxycarbonylpropoxy,ethoxycarbonylmethoxy, 4-ethoxycarbonylbutoxy,6-propoxycarbonylhexyloxy, 5-isopropoxycarbonylpentyloxy,1,1-dimethyl-2-butoxycarbonylethoxy,2-methyl-3-tert-butoxycarbonylpropoxy, 2-pentyoxycarbonylethoxy,hexyloxycarbonylmethoxy and the like.

As to the carboxy-substituted lower alkoxy group, there can be mentionedcarboxyalkoxy groups each having a C₁₋₆ straight-chain or branched-chainalkoxy moiety, such as carboxymethoxy, 2-carboxyethoxy, 1-carboxyethoxy,3-carboxypropyl, 4-carboxybutoxy, 5-carboxypentyloxy, 6-carboxyhexyloxy,1,1-dimethyl-2-carboxyethoxy, 2-methyl-3-carboxypropoxy and the like.

As to the lower alkoxy-substituted alkoxy group, there can be mentionedalkoxyalkoxy groups each having a C₁₋₆ straight-chain or branched-chainalkoxy moiety, such as methoxymethoxy, 3-methoxypropoxy, ethoxymethoxy,4-ethoxybutoxy, 6-propoxyhexyloxy, 5-isopropoxypentyloxy,1,1-dimethyl-2-butoxyethoxy, 2-methyl-3-tert-butoxypropoxy,2-pentyloxyethoxy, hexyloxymethoxy and the like.

The lower alkyl group having hydroxyl groups can be exemplified by C₁₋₆straight-chain or branched-chain alkyl groups each having one to threehydroxyl groups, such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl,3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl,1,1-dimethyl-2-hydroxyethy, 5,5,4-trihydroxypentyl, 5-hydroxypentyl,6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl and thelike.

The lower alkenyl group can be exemplified by C₁₋₆ straight-chain orbranched-chain alkenyl groups such as vinyl, allyl, 2-butenyl,3-butenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl and the like.

The aminothiocarbonyloxy group which may have lower alkyl groups assubstituents, can be exemplified by thiocarbonyloxy groups each havingan amino group which may have one to two C₁₋₆ straight-chain orbranched-chain alkyl groups as substituent(s), such as thiocarbamoyloxy,methylaminothiocarbonyloxy, ethylaminothiocarbonyloxy,propylaminothiocarbonyloxy, isopropylaminothiocarbonyloxy,butylaminothiocarbonyloxy, pentylaminothiocarbonyloxy,hexylaminothiocarbonyloxy, dimethylaminothiocarbonyloxy,(N-ethyl-N-propylamino)thiocarbonyloxy,(N-methyl-N-hexylamino)thiocarbonyloxy and the like.

The aminocarbonylthio group which may have lower alkyl groups assubstituents, can be exemplified by carbonylthio groups having an aminogroup which may have one to two C₁₋₆ straight-chain or branched-chainalkyl groups as substituent(s), such as aminocarbonylthio,methylaminocarbonylthio, ethylaminocarbonylthio,propylaminocarbonylthio, 3-isopropylaminocarbonylthio,butylaminocarbonylthio, pentylaminocarbonylthio, hexylaminocarbonylthio,dimethylaminocarbonylthio, (N-ethyl-N-propylamino)carbonylthio,(N-methyl-N-hexylamino)carbonylthio and the like.

As to the lower alkanoyl-substituted lower alkyl group, there can bementioned C₁₋₆ straight-chain or branched-chain alkyl groups each havingone to three C₁₋₆ straight-chain or branched-chain alkanoyl groups, suchas formylmethyl, acetylmethyl, 2-propionylethyl, 1-butyrylethyl,3-acetylpropyl, 2,3-diacetylpropyl, 4-isobutyrylbutyl,5-pentanoylpentyl, 6-tert-butylcarbonylhexyl,1,1-dimethyl-2-hexanoylethyl, 5,5,4-triacetylpentyl,2-methyl-3-acetylpropyl and the like.

The phenyl group which may have one to three lower alkoxy groups assubstituents on the phenyl ring, can be exemplified by phenyl ringswhich may each have one to three C₁₋₆ straight-chain or branched-chainalkoxy groups as substituents on the phenyl ring, such as phenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl,3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-pentyloxyphenyl,4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3-ethoxy-4-methoxyphenyl,2,3-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,5-dimethoxyphenyl,2,6-dimethoxyphenyl, 3-propoxy-4-methoxyphenyl, 3,5-dimethoxyphenyl,3,4-dipentyloxyphenyl, 3,4,5-trimethoxyphenyl, 3-methoxy-4-ethoxyphenyland the like.

The pyridyl group which may have an oxo group, can be exemplified bypyridyl groups which may each have an oxo group, such as 2-pyridyl,3-pyridyl, 4-pyridyl, 2-oxo-3-pyridyl, 4-oxo-2-pyridyl, 1-oxo-3-pyridyl,3-oxo-2-pyridyl and the like.

The quinolyl group which may have an oxo group, can be exemplified byquinolyl groups which may each have an oxo group, such as 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl,2-oxo-4-quinolyl, 2-oxo-7-quinolyl, 2-oxo-5-quinolyl, 2-oxo-8-quinolyl,4-oxo-6-quinolyl and the like.

The phenyl group having, as substituents on the phenyl ring, one tothree groups selected from the group consisting of a lower alkanoyloxygroup, a hydroxysulfonyloxy group, a cyano group, an amidino group, anitro group, a lower alkylsulfonyl group and a tetrahydropyranyloxygroup which may have, as substituents, one to four groups selected fromthe group consisting of a hydroxyl group, a lower alkoxycarbonyl group,a phenyl-lower alkoxy group, a lower alkanoyloxy-substituted lower alkylgroup and a lower alkanoyloxy group, can be exemplified by phenyl groupseach having, as substituent(s) on the phenyl ring, one to three groupsselected from the group consisting of a C₁₋₆ straight-chain orbranched-chain alkanoyloxy group, a hydroxysulfonyloxy group, a cyanogroup, an amidino group, a nitro group, a C₁₋₆ straight-chain orbranched-chain alkylsulfonyl group and a tetrahydropyranyloxy groupwhich may have, as substituents, one to four groups selected from thegroup consisting of a hydroxyl group, a C₁₋₆ straight-chain orbranched-chain alkoxycarbonyl group, a phenylalkoxy group having a C₁₋₆straight-chain or branched-chain alkoxy moiety, a C₁₋₆ straight-chain orbranched-chain alkyl group having one to three C₂₋₆ straight-chain orbranched-chain alkanoyloxy groups, and a C₂₋₆ straight-chain orbranched-chain alkanoyloxy group, such as 2-acetyloxyphenyl,3-acetyloxyphenyl, 4-acetyloxyphenyl, 2-formyloxyphenyl,3-propionyloxyphenyl, 4-isobutyryloxyphenyl, 2-pentanoyloxyphenyl,3-hexanoyloxyphenyl, 3,4-diacetyloxyphenyl, 2,5-diacetyloxyphenyl,3,5-diacetyloxyphenyl, 2,5-diacetyloxyphenyl, 3,4,5-triaceyloxyphenyl,4-hydroxysulfonyloxyphenyl, 3-hydroxysulfonyloxyphenyl,2-hydroxysulfonyloxyphenyl, 4-cyanophenyl, 3-cyanophenyl, 2-cyanophenyl,4-amidinophenyl, 3-amidinophenyl, 2-amidinophenyl, 2-nitrophenyl,3-nitrophenyl, 4-nitrophenyl, 3,4-dinitrophenyl, 2,5-dinitrophenyl,2,6-dinitrophenyl, 3,4,5-trinitrophenyl, 3,5-dinitro-4-acetyloxyphenyl,4-methylsulfonylphenyl, 2-methylsulfonylphenyl, 3-methylsulfonylphenyl,2-ethylsulfonylphenyl, 4-isopropylsulfonylphenyl,4-pentylsulfonylphenyl, 4-hexylsulfonylphenyl,3,4-dimethylsulfonylphenyl, 3,4-diethylsulfonylphenyl,2,5-dimethylsulfonylphenyl, 2,6-dimethylsulfonylphenyl,3,4,5-trimethylsulfonylphenyl,4-(2,3,4,6-tetra-o-acetyl-β-D-glucopyranosyloxy)phenyl,4-(β-D-glucopyranosyloxy)phenyl,4-(2,3,4,6-tetra-o-benzyl-β-D-glucopyranosyloxy)phenyl and the like.

The amino group which may have a lower alkanoyl group, can beexemplified by amino groups which may each have a C₁₋₆ straight-chain orbranched-chain alkanoyl group, such as amino, formylamino, acetylamino,propionylamino, butyrylamino, isobutyrylamino, pentanoylamino,tertbutylcarbonylamino, pentanoylamino, hexanoylamino and the like.

The phenyl group which may have groups selected from the groupconsisting of a thiazolyl group having, as a substituent on thethiazolyl ring, a phenyl group which may have lower alkoxy groups on thephenyl ring, a carboxyl group and a hydroxyl group, can be exemplifiedby phenyl groups which may each have one to three groups selected fromthe group consisting of a thiazolyl group having, as a substituent onthe thiazolyl ring, a phenyl group which may have one to three C₁₋₆straight-chain or branched-chain alkoxy groups on the phenyl ring, acarboxyl group and a hydroxyl group, such as phenyl,2-(3,4-diethoxyphenyl)-4-thiazolylphenyl,2-(4-methoxyphenyl)-4-thiazolyl!phenyl,4-(3,4,5-trimethoxyphenyl)-2-thiazolyl!phenyl,5-(3-propoxyphenyl)-2-thiazolyl!-phenyl,2-(2-butoxyphenyl)-4-thiazolyl!phenyl, 2-hydroxy-3-carboxyphenyl,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl,3,5-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,4-dihydroxyphenyl,2,6-dihydroxyphenyl, 3,4,5-trihydroxyphenyl, 2-carboxyphenyl,3-carboxyphenyl, 4-carboxyphenyl, 3,4-dicarboxyphenyl,2,5-dicarboxyphenyl, 2,6-dicarboxyphenyl, 3,4,5-tricarboxyphenyl,3-carboxy-4-hydroxyphenyl, 3-carboxy-6-hydroxyphenyl and the like.

As the piperidinyl-lower alkyl group, there can be mentionedpiperidinylalkyl groups each having a C₁₋₆ straight-chain orbranched-chain alkyl moiety, such as (1-piperidinyl)methyl,2-(1-piperidinyl)ethyl, 1-(1-piperidinyl)ethyl, 3-(1-piperidinyl)propyl,4-(1-piperidinyl)butyl, 5-(2-piperidinyl)pentyl, 6-(3-piperidinyl)hexyl,1,1-dimethyl-2-(4-piperidinyl)ethyl, 2-methyl-3-(1-piperidinyl)propyland the like.

The alkoxycarbonyl group can be exemplified by, in addition to theabove-mentioned lower alkoxycarbonyl groups, C₁₋₁₈ straight-chain orbranched-chain alkoxycarbonyl groups, such as heptyloxycarbonyl,octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl,undecyloxycarbonyl, dodecyloxycarbonyl, tridecyloxycarbonyl,tetradecyloxycarbonyl, pentadecyloxycarbonyl, hexadecyloxycarbonyl,heptadecyloxycarbonyl, octadecyloxyqarbonyl and the like.

The amino-lower alkoxycarbonyl group which may have a lower alkyl groupas a substituent, can be exemplified by C₁₋₆ straight-chain orbranched-chain alkoxycarbonyl groups each having an amino group whichmay have one to two C₁₋₆ straight-chain or branched-chain alkyl groupsas substituents, such as aminomethoxycarbonyl, 2-aminoethoxycarbonyl,1-aminoethoxycarbonyl, 3-aminopropoxycarbonyl, 4-aminobutoxycarbonyl,5-aminopentyloxycarbonyl, 6-aminohexyloxycarbonyl,1,1-dimethyl-2-aminoethoxycarbonyl, 2-methyl-3-aminopropoxycarbonyl,methylaminomethoxycarbonyl, 1-ethylaminoethoxycarbonyl,2-propylaminoethoxycarbonyl, 3-isopropylaminopropoxycarbonyl,4-butylaminobutoxycarbonyl, 5-pentylaminopentyloxycarbonyl,6-hexylaminohexyloxycarbonyl, dimethylaminomethoxycarbonyl,2-dimethylaminoethoxycarbonyl, 3-dimethylaminopropoxycarbonyl,(N-ethyl-N-propylamino)methoxycarbonyl,2-(N-methyl-N-hexylamino)ethoxycarbonyl and the like.

The phenyl-lower alkoxycarbonyl group can be exemplified byphenylalkoxycarbonyl groups each having a C₁₋₆ straight-chain orbranched-chain alkoxy moiety, such as benzyloxycarbonyl,2-phenylethoxycarbonyl, 1-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl,4-phenylbutoxycarbonyl, 1,1-dimethyl-2-phenylethoxycarbonyl,5-phenylpentyloxycarbonyl, 6-phenylhexyloxycarbonyl,2-methyl-3-phenylpropoxycarbonyl and the like.

The lower alkynyl group there can be mentioned alkynyl groups eachhaving C₂₋₆ straight-chain or branched-chain alkynyl moiety, such asethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl,2-pentynyl, 2-hexynyl and the like.

As to the carboxy-substituted lower alkyl group, there can be mentionedcarboxyalkyl groups each having a C₁₋₆ straight-chain or branched-chainalkyl moiety, such as carboxymethyl, 2-carboxyethyl, 1-carboxyethyl,3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl,1,1-dimethyl-2-carboxyethyl, 2-methyl-3-carboxypropyl and the like.

As to the lower alkoxycarbonyl-lower alkenyl group, there can bementioned alkoxycarbonylalkenyl groups each having a C₁₋₆ straight-chainor branched-chain alkoxy moiety and a C₂₋₆ straight-chain orbranched-chain alkenyl moiety, such as 2-methoxycarbonylvinyl,3-methoxycarbonylallyl, 2-ethoxycarbonylvinyl,4-ethoxycarbonyl-2-butenyl, 6-propoxycarbonyl-3-hexenyl,5-isopropoxycarbonyl-1-pentenyl,1,1-dimethyl-2-butoxycarbonyl-2-propenyl,2-methyl-3-tertbutoxycarbonyl-1-propenyl, 2-pentyloxycarbonylvinyl,4-hexyloxycarbonyl-1-butenyl and the like.

As to the carboxy-substituted lower alkenyl group, there can bementioned carboxyalkenyl groups each having a C₂₋₆ straight-chain orbranched-chain alkenyl moiety, such as 2-carboxyvinyl, 3-carboxyallyl,4-carboxy-2-butenyl, 6-carboxy-3-hexenyl, 5-carboxy-1-pentenyl,1,1-dimethyl-2-carboxy-2-propenyl, 2-methyl-3-carboxy-1-propenyl,5-carboxy-4-pentenyl, 4-carboxy-1-butenyl and the like.

The five- or six-membered saturated heterocyclic ring which R²³ and R²⁴as well as the adjacent nitrogen atom being bonded thereto may formtogether with or without other nitrogen atom or oxygen atom, can beexemplified by piperazinyl, pyrrolidinyl, morpholinyl and piperidinyl.

The above heterocyclic ring substituted with a lower alkyl group can beexemplified by above heterocyclic rings each substituted with a C₁₋₆straight-chain or branched-chain alkyl group, such as4-methylpiperazinyl, 4-ethylpiperazinyl, 3-ethylpyrrolidinyl,2-propylpyrrolidinyl, 4-butylpiperidinyl, 3-pentylmorpholino,2-hexylpiperazinyl and the like.

The lower alkylsulfonyloxy group which may have halogen atoms, can beexemplified by C₁₋₆ straight-chain or branched-chain alkylsulfonyloxygroups which may each have one to three halogen atoms, such asmethylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy,isopropylsulfonyloxy, butylsulfonyloxy, tert-butylsulfonyloxy,pentylsulfonyloxy, hexylsulfonyloxy, chloromethylsulfonyloxy,bromomethylsulfonyloxy, iodomethylsulfonyloxy,trifluoromethylsulfonyloxy, 2-fluoroethylsulfonyloxy,2,2-difluoroethylsulfonyloxy, 2,2,2-trifluoroethylsulfonyloxy,3-chloropropylsulfonyloxy, 4-chlorobutylsulfonyloxy,3,4-dichlorobutylsulfonyloxy, 3-fluoropentylsulfonyloxy,2,3,4-trifluoropentylsulfonyloxy, 2,3-dichlorohexylsulfonyloxy,6,6-dibromohexylsulfonyloxy and the like.

As the lower alkoxy-substituted lower alkoxycarbonyl group, there can bementioned C₁₋₆ straight-chain or branched-chain alkoxyalkoxycarbonylgroups each having a C₁₋₆ straight-chain or branched-chain alkoxymoiety, such as methoxymethoxycarbonyl, 3-methoxypropoxycarbonyl,ethoxymethoxycarbonyl, 4-ethoxybutoxycarbonyl,6-propoxyhexyloxycarbonyl, 5-isopropoxypentyloxycarbonyl,1,1-dimethyl-2-butoxyethoxycarbonyl,2-methyl-3-tertbutoxypropoxycarbonyl, 2-pentyloxyethoxycarbonyl,hexyloxymethoxycarbonyl and the like.

The phenyl group which may have one to three lower alkoxy groups assubstituents on the phenyl ring, can be exemplified by phenyl groupswhich may each have one to three C₁₋₆ straight-chain or branched-chainalkoxy groups as substituents on the phenyl ring, such as phenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-ethoxyphenyl, 2-ethoxyphenyl,3-ethoxyphenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 3-butoxyphenyl,4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl,3-ethoxy-4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-diethoxyphenyl,3,5-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl,3,4,5-trimethoxyphenyl, 3,4-dipentyloxyphenyl and the like.

The pyridyl group which may have an oxo group, can be exemplified bypyridyl groups which may each have an oxo group, such as pyridyl,2-oxopyridyl, 3-oxopyridyl, 4-oxopyridyl and the like.

The quinolyl group which may have an oxo group, can be exemplified by2-oxoquinolyl and 4-oxoquinolyl.

The phenyl group having, as substituent(s) on the phenyl ring, one tothree groups selected from the group consisting of a lower alkanoyloxygroup, a hydroxysulfonyloxy group, a cyano group, an amidino group, anitro group, a lower alkylsulfonyl group, a tetrahydropranyloxy groupwhich may have, as substituent(s), one to four groups selected from thegroup consisting of a hydroxyl group, a lower alkoxycarbonyl group, aphenyl-lower alkoxy group, a hydroxyl group- or lower alkanoyloxygroup-substituted lower alkyl group and a lower alkanoyloxy group, aphenyl group which may have groups selected from the group consisting ofa thiazolyl group having, as a substituent on the thiazolyl ring, aphenyl group which may have lower alkoxy groups on the phenyl ring, acarboxyl group and a hydroxyl group, a lower alkyl group having hydroxylgroups, and a group ##STR35## (wherein R²¹ and R²² are the same asdefined above), can be exemplified by phenyl groups each having, assubstituent(s) on the phenyl ring, one to three groups selected from thegroup consisting of a C₁₋₆ straight-chain or branched-chain alkanoyloxygroup, a hydroxysulfonyloxy group, a cyano group, an amidino group, anitro group, a C₁₋₆ straight-chain or branched-chain alkylthio group, aC₁₋₆ straight-chain or branched-chain alkylsulfonyl group, atetrahydropranyloxy group which may have, as substituents, one to fourgroups selected from the group consisting of a hydroxyl group, a C₁₋₆straight-chain or branched-chain alkoxycarbonyl group, a phenylalkoxygroup having a C₁₋₆ straight-chain or branched-chain alkoxy moiety, aC₁₋₆ straight-chain or branched-chain alkyl group having one to threehydroxyl groups or one to three C₂₋₆ straight-chain or branched-chainalkanoyloxy groups and a C₂₋₆ straight-chain or branched-chainalkanoyloxy group, a phenyl group which may have one to three groupsselected from the group consisting of a thiazolyl group having, as asubstituent on the thiazolyl ring, a phenyl group which may have one tothree C₁₋₆ straight-chain or branched-chain alkoxy groups on the phenylring, a carboxyl group and a hydroxyl group, a C₁₋₆ straight-chain orbranched-chain alkyl group having one to three hydroxyl groups, and agroup ##STR36## (wherein R²¹ and R²², which may be the same ordifferent, each represent a hydrogen atom or a C₁₋₆ straight-chain orbranched-chain alkyl group), such as 2-methylthiophenyl,3-methylthiophenyl, 4-methylthiophenyl, 2-ethylthiophenyl,3-ethylthiophenyl, 4-ethylthiophenyl, 4-isopropylthiophenyl,4-pentylthiophenyl, 4-hexylthiophenyl, 3,4-dimethylthiophenyl,3,4-diethylthiophenyl, 2-acetyloxyphenyl, 3-acetyloxyphenyl,4-acetyloxyphenyl, 2-formyloxyphenyl, 3-propionyloxyphenyl,4-isobutyryloxyphenyl, 2-pentanoyloxyphenyl, 3-hexanoyloxyphenyl,3,4-diacetyloxyphenyl, 3,5-diacetyloxyphenyl, 2,5-diacetyloxyphenyl,3,4,5-triacetyloxyphenyl-dimethylthiophenyl, 2,6-dimethylthiophenyl,3,4,5-trimethylthiophenyl, 3-phenylphenyl, 4-phenylphenyl,2-methylsulfonylphenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl,2-ethylsulfonylphenyl, 4-isopropylsulfonylphenyl,4-pentylsulfonylphenyl, 4-hexylsulfonylphenyl,3,4-dimethylsulfonylphenyl, 2,5-dimethylsulfonylphenyl,2,6-dimethylsulfonylphenyl, 3,4,5-trimethylsulfonylphenyl,2-amidinophenyl, 4-amidinophenyl, 3-amidinophenyl, 3-nitrophenyl,4-hydroxysulfonyloxyphenyl, 3-hydroxysulfonyloxyphenyl,2-hydroxysulfonyloxyphenyl,4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)phenyl,4-(β-D-glucopyranosyloxy)phenyl,4-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyloxy)phenyl,3,5-bis(dimethylamino)phenyl, 2-nitrophenyl, 4-nitrophenyl,3,4-dinitrophenyl, 3,4,5-trinitrophenyl, 3,5-dinitrophenyl,2-cyanophenyl, 4-cyanophenyl, 3-cyanophenyl,3-(2,3-dihydroxypropyl)phenyl, 3-(2-hydroxyethyl)phenyl,4-(2-hydroxy-3-carboxyphenyl)phenyl, 4-2-(3,4-diethoxyphenyl-4-thiazolyl!phenyl, 3-hydroxymethylphenyl,##STR37## and the like.

As to the lower alkoxy-substituted lower alkyl group, there can bementioned alkoxyalkyl groups each having a C₁₋₆ straight-chain orbranched-chain alkoxy moiety and a ₁₋₆ straight-chain or branched-chainalkyl moiety, such as methoxymethyl, 3-methoxypropyl, ethoxymethyl,4-ethoxybutyl, 6-propoxyhexyl, 5-isopropoxypentyl,1,1-dimethyl-2-butoxyethyl, 2-methyl-3-tert-butoxypropyl,2-pentyloxyethyl, hexyloxymethyl and the like.

The lower alkenyl group having halogen atoms can be exemplified by C₂₋₆straight-chain or branched-chain alkenyl groups each having one to threehalogen atoms, such as 2,2-dibromovinyl, 2-chlorovinyl, 1-fluorovinyl,3-iodoallyl, 4,4-dichloro-2-butenyl, 4,4,3-tribromo-3-butenyl,3-chloro-1-methylallyl, 5-bromo-2-pentenyl, 5,6-difluoro-2-hexenyl andthe like.

As the phenyl-lower alkyl group, there can be mentioned phenylalkylgroups each having a C₁₋₆ straight-chain or branched-chain alkyl moiety,such as benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl,4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl,1,1-dimethyl-2-phenylethyl, 2-methyl-3-phenylpropyl and the like.

The compound of general formula (I) according to the present inventioncan be produced by, for example, the processes shown below. ##STR38##(wherein X, R¹, R² and R³ are the same as defined above; Y represents ahalogen atom).

The reaction between the compound (2) and the compound (3) can beconducted by heating in an appropriate solvent. The solvent can beexemplified by alcohols such as methanol, ethanol, propanol, butanol,3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve and the like;aromatic hydrocarbons such as benzene, toluene, xylene,o-dichlorobenzene and the like; ethers such as diethyl ether,tetrahydrofuran, dioxane, diglyme, monoglyme and the like; halogenatedhydrocarbons such as dichloromethane, chloroform, carbon tetrachlorideand the like; polar solvents such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, acetonitrile and the like; andmixed solvents thereof. The reaction is conducted ordinarily at roomtemperature to 150° C., preferably at about room temperature to 100° C.and is completed in about 1-15 hours.

The proper amount of the compound (3) used is at least 1 mole,preferably about 1 to 1.5 moles per 1 mole of the compound (2).##STR39## (wherein R¹, R², R³ and Y are the same as defined above).

The reaction between the compound (2) and the compound (4) can beconducted in an appropriate solvent in the presence of a basic compound.The solvent can be exemplified by lower alcohols such as methanol,ethanol, propanol and the like; ethers such as diethyl ether,tetrahydrofuran, dioxane, ethylene glycol monomethyl ether and the like;halogenated hydrocarbons such as dichloromethane, chloroform, carbontetrachloride and the like; aromatic hydrocarbons such as benzene,toluene, xylene and the like; esters such as methyl acetate, ethylacetate and the like; ketones such as acetone, methyl ethyl ketone andthe like; polar solvents such as acetonitrile, dimethylformamide,dimethyl sulfoxide, hexamethylphosphoric triamide and the like; andmixed solvents thereof. The basic compound can be exemplified byinorganic bases such as sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium hydride and the like; alkali metals such asmetallic sodium, metallic potassium and the like; alkali metalalcoholates such as sodium methylate, sodium ethylate and the like; andorganic bases such as triethylamine, pyridine, N,N-dimethylaniline,N-methylmorpholine, 4-methylaminopyridine, bicyclo 4,3,0!nonene-5 (DBN),1,8-diazabicyclo 5,4,0!-undecene-7 (DBU), 1-4-diazabicyclo 2,2,2!octane(DABCO) and the like.

The proper amount of the compound (4) used is at least 1 mole,preferably about 1 to 1.5 moles per 1 mole of the compound (2).

The reaction is conducted ordinarily at room temperature to 200° C.,preferably at room temperature to about 150° C. and is completed inabout 1-5 hours.

The reaction for converting the compound (5) into the compound (1a) canbe conducted in an appropriate solvent in the presence of an ammoniawater or an ammonium salt such as ammonium acetate, ammonium chloride,ammonium sulfate or the like. The solvent can be any of the solventsusable in the reaction between the compound (2) and the compound (4);besides them, there can also be mentioned alkanoic acids (e.g. aceticacid), etc. The proper amount of the ammonia water or ammonium salt usedis at least 1 mole, preferably 1 to 5 moles per 1 mole of the compound(5). The reaction is conducted ordinarily at room temperature to 200°C., preferably at about room temperature to 150° C. and is completed inabout 1-5 hours. ##STR40## (wherein R¹, R² and R³ are the same asdefined above).

The reaction between the compound (6) and the compound (4) can beachieved by subjecting them to an ordinary amide bonding formationreaction.

In this case, as to the carboxylic acid (4), an activated compoundthereof may be used. The conditions used in the amide bonding formationreaction can be those used in ordinary amide bonding formationreactions. For example, there can be used (a) a mixed acid anhydridemethod, i.e. a method which comprises reacting a carboxylic acid (4)with an alkylhalocarboxylic acid to obtain a mixed acid anhydride andreacting the anhydride with a compound (6); (b) an active ester oractive amide method, i.e. a method which comprises converting acarboxylic acid (4) into an active ester such as p-nitrophenyl ester,N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester or the like, orinto an active amide with benzoxazolin-2-thion and then reacting theactive ester or active amide with a compound (6); (c) a carbodiimidemethod, i.e. a method which comprises subjecting a carboxylic acid (4)and a compound (6) to dehydration in the presence of a dehydrating agentsuch as dicyclohexylcarbodiimide, carbonyldiimidazole or the like; (d) acarboxylic acid halide method, i.e. a method which comprises convertinga carboxylic acid (4) into a halide and reacting the halide with acompound (6); and (e) other methods such as a method which comprisesreacting a carboxylic acid (4) with a dehydrating agent such as aceticanhydride or the like to convert into a carboxylic acid anhydride andreacting the anhydride with a compound (4) or a method which comprisesconverting a carboxylic acid (4) into an ester and reacting the esterwith a compound (6) at a high temperature at a high pressure. There canalso be used a method which comprises activating a carboxylic acid (4)with a phosphorus compound such as triphenylphosphine, diethylchlorophosphate or the like and reacting the reaction product with acompound (6).

As to the alkylhalocarboxylic acid used in the mixed acid anhydridemethod, there can be mentioned, for example, methyl chloroformate,methyl bromoformate, ethyl chloroformate, ethylbromoformate and isobutylchloroformate. The mixed acid anhydride can be obtained by an ordinarySchotten-Baumann reaction and ordinarily, without being subjected to anisolation procedure, is reacted with a compound (6), whereby a compound(7) can be produced. The Schotten-Baumann reaction is ordinarilyconducted in the presence of a basic compound. The basic compound isthose conventionally used in the Schotten-Baumann reaction; and therecan be mentioned organic bases such as triethylamine, trimethylamine,pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine,DBN, DBU, DABCO and the like, and inorganic bases such as potassiumcarbonate, sodium carbonate, potassium hydrogencarbonate, sodiumhydrogencarbonate and the like. The reaction is conducted at about -20°C. to 100° C., preferably 0°-50° C. The reaction time is about 5 minutesto 10 hours, preferably 5 minutes to 2 hours. The reaction between thethus obtained mixed acid anhydride and the compound (6) is conducted atabout -20° C. to 150° C., preferably 10°-50° C. for about 5 minutes to10 hours, preferably about 5 minutes to 5 hours. The mixed acidanhydride method needs no solvent, but is generally conducted in asolvent. The solvent can be any of those conventionally used in themixed acid anhydride method, and there can be specifically mentioned,for example, halogenated hydrocarbons such as methylene chloride,chloroform, dichloroethane and the like, aromatic hydrocarbons such asbenzene, toluene, xylene and the like, ethers such as diethyl ether,diisopropyl ether, tetrahydrofuran, dimethoxyethane and the like, esterssuch as methyl acetate, ethyl acetate and the like, and aprotic polarsolvents such as dimethylformamide, dimethyl sulfoxide,hexamethylphosphoric triamide and the like. In the above method, theamounts of the carboxylic acid (4), the alkylhalocarboxylic acid and thecompound (6) used are ordinarily at least equimolar, but preferably thealkylhalocarboxylic acid and the compound (6) are used each in an amountof i-2 moles per 1 mole of the carboxylic acid (4).

The active ester or active amide method (b), when a case of using, forexample, benzoxazolin-2-thionamide is mentioned, is conducted bycarrying out a reaction at 0°-150° C., preferably 10°-100° C. for 0.5-75hours in an appropriate solvent not affecting the reaction, for example,the same solvent as used in the above mixed acid anhydride method, or1-methyl-2-pyrrolidone. The amounts of the compound (6) andbenzoxazolin-2-thionamide used are such that the latter is used in anamount of at least 1 mole, preferably 1-2 moles per 1 mole of theformer. In a case using an N-hydroxysuccinimide ester, the reactionproceeds advantageously by using an appropriate base, for example, thesame base as used in the carboxylic acid halide method to be describedlater.

The carboxylic acid halide method (c) is conducted by reacting acarboxylic acid (4) with a halogenating agent to convert into acarboxylic acid halide and, after or without isolating and purifying thehalide, reacting the halide with a compound (6). The reaction betweenthe carboxylic acid halide and the compound (6) is conducted in anappropriate solvent in the presence or absence of a dehydrohalogenatingagent. As to the dehydrohalogenating agent, there is ordinarily used abasic compound, and there can be mentioned the basic compounds used inthe above Schotten-Baumann reaction, sodium hydroxide, potassiumhydroxide, sodium hydride, potassium hydride, alkali metal alcholates(e.g. sodium methylate, sodium ethylate), etc. Incidentally, it ispossible to use the compound (6) in an excessive amount to utilize thecompound (6) also as a dehydrohalogenating agent. As the solvent, therecan be mentioned, for example, water, alcohols (e.g. methanol, ethanol,propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methylcellosolve), pyridine, acetone, acetonitrile and mixed solvents thereof,in addition to the same solvents as used in the above Schotten-Baumannreaction. The proportions of the compound (6) and the carboxylic acidhalide used are not particularly restricted and can be selected from awide range, but the latter is used in an amount of ordinarily at least 1mole, preferably 1-5 moles per 1 mole of the former. The reaction isconducted ordinarily at about -30° C. to 180° C., preferably at about0°-150° C. and is complete generally in 5 minutes to 30 hours. Thecarboxylic acid halide used is produced by reacting a carboxylic acid(4) with a halogenating agent in the presence or absence of a solvent.The solvent can be any as long as it gives no influence on the reaction,and includes aromatic hydrocarbons Such as benzene, toluene, xylene andthe like, halogenated hydrocarbons such as chloroform, methylenechloride, carbon tetrachloride and the like, ethers such as dioxane,tetra-hydrofuran, diethyl ether and the like, dimethylformamide,dimethyl sulfoxide, etc. As the halogenating agent, there can be usedordinary halogenating agents capable of converting the hydroxyl group ofcarboxylic group into a halogen, and there can be mentioned, forexample, thionyl chloride, oxalyl chloride, phosphorus oxychloride,phosphorus oxybromide, phosphorus pentachloride and phosphoruspentabromide. The proportions of the carboxylic acid (4) and thehalogenating agent used are not particularly restricted and can beselected appropriately; however, when the reaction is conducted in asolventless state, the latter is used ordinarily in a large excessrelative to the former and, when the reaction is conducted in a solvent,the latter is used in an amount of ordinarily at least about 1 mole,preferably 2-4 moles per 1 mole of the former. The reaction temperatureand time are not particularly restricted, either, but the reaction isconducted ordinarily at about room temperature to 100° C., preferably at50°-80° C. for about 30 minutes to 6 hours.

The method which comprises activating a carboxylic acid (4) with aphosphorus compound such as triphenylphosphine, diethyl chlorophosphate,diethyl cyanophosphate or the like and then reacting the resultingproduct with a compound (6), is conducted in an appropriate solvent. Thesolvent can be any as long as it gives no influence on the reaction, andspecifically includes halogenated hydrocarbons such as dichloromethane,chloroform, dichloroethane and the like, aromatic hydrocarbons such asbenzene, toluene, xylene and the like, ethers such as diethyl ether,tetrahydrofuran, dimethoxyethane and the like, esters such as methylacetate, ethyl acetate and the like, aprotic polar solvents such asdimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide andthe like, and so forth. In the reaction, the compound (6) per se acts asa basic compound, and accordingly the reaction proceeds advantageouslyby using it in an amount larger than the stoichiometric amount; however,there may be used, as necessary, other basic compound, for example, anorganic base (e.g. triethylamine, trimethylamine, pyridine,dimethylaminopyridine, DBN, DBU, DABCO) or an inorganic base (e.g.potassium carbonate, sodium carbonate, potassium hydrogencarbonate,sodium hydrogencarbonate). The reaction is conducted at about 0°-150°C., preferably at about 0°-100° C. and is complete in about 1-30 hours.The proportions of the phosphorus compound and carboxylic acid (4) usedrelative to the compound (6) are each ordinarily at least about 1 mole,preferably 1-3 moles per 1 mole of the compound (6).

The reaction for converting the compound (7) into the compound (1b) canbe conducted in a solventless state or in an appropriate solvent in thepresence of a sulfurizing agent such as2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide(Lawesson's Reagent), phosphorus pentasulfide or the like. The solventcan be any of those used in the reaction between the compound (2) andthe compound (4) in the above Reaction scheme-2.

The proper amount of the sulfurizing agent used is ordinarily 0.5-2moles, preferably 0.5-1.5 moles per 1 mole of the compound (7).

The reaction is conducted ordinarily at 50°-300° C., preferably at about50° C. to 250° C. and is completed in about 1-7 hours.

The compound (2) as a starting material can be produced by, for example,the method of the following Reaction scheme-4 or -5. ##STR41## (whereinR², R³ and Y are the same as defined above).

The halogenation reaction for the compound (8) can be conducted in anappropriate solvent in the presence of a halogenating agent. Thehalogenating agent can be exemplified by halogen molecules (e.g. brominemolecules, chlorine molecules), iodine chloride, sulfuryl chloride,copper compounds (e.g. cuprous bromide) and N-halogenated succinimides(e.g. N-bromosuccinimide, N-chlorosuccinimide). The solvent can beexemplified by halogenated hydrocarbons (e.g. dichloromethane,dichloroethane, chloroform, carbon tetrachloride), fatty acids (e.g.acetic acid, propionic acid) and carbon disulfide.

The proper amount of the halogenating agent used is ordinarily 1-10moles, preferably 1-5 moles per 1 mole of the compound (8).

The reaction is conducted ordinarily at 0° C. to the boiling point ofthe solvent used, preferably at about 0° C. to 100° C. and is completedordinarily in about 5 minutes to 20 hours. ##STR42## (wherein R² and Yare the same as defined above; Y₁ represents a halogen atom; R^(3')represents the above-mentioned R³ other than a hydrogen atom, a loweralkyl group, a lower alkoxycarbonyl-lower alkyl group, a loweralkoxycarbonyl group, a carbamoyl-lower alkyl group, a phenyl-loweralkyl group which may have a lower alkoxy group as a substituent on thephenyl ring and hydroxyl groups as substituents on the lower alkylgroup, a benzoyl group which may have a lower alkoxy group as asubstituent on the phenyl ring, a phenyl-lower alkenyl group which mayhave a lower alkoxy group as a substituent on the phenyl ring, and anadamantyl group).

The reaction between the compound (9) and the compound (10) or thecompound (11) is generally called as Friedel-Crafts reaction and can beconducted in an appropriate solvent in the presence of a Lewis acid. TheLewis acid can be any one of Lewis acids generally used in saidreaction, and can be exemplified by aluminum chloride, zinc chloride,iron chloride, tin chloride, boron tribromide, boron trifuloride andconcentrated sulfuric acid. The solvent can be exemplified by carbondisulfide, aromatic hydrocarbons (e.g. nitrobenzene, chlorobenzene) andhalogenated hydrocarbons (e.g. dichloromethane, dichloroethane, carbontetrachloride, tetrachloroethane). The proper amount of the compound(10) or the compound (11) used is at least 1 mole, preferably 1-5 molesper 1 mole of the compound (9). The proper amount of the Lewis acid usedis ordinarily 2-6 moles per 1 mole of the compound (9).

The reaction is conducted ordinarily at 0°-120° C., preferably at about0°-70° C. and is completed in about 0.5-24 hours.

The compound (3) as a starting material can be produced by, for example,the method of the following Reaction scheme-6 or -7. ##STR43## (R¹ isthe same as defined above; R⁴ represents a lower alkyl group).

The reaction between the compound (12) and the compound (13) can beconducted in an appropriate solvent in the presence of an acid.

The solvent can be any of those used in the reaction between thecompound (2) and the compound (4) in the reaction scheme 2.

The acid can be exemplified by mineral acids such as hydrochloric acid,hydrobromic acid, sulfuric acid and the like.

The amount of the compound (13) used is ordinarily 1-5 moles, preferably1-3 moles per 1 mole of the compound (12).

The reaction is conducted ordinarily at room temperature to 200° C.,preferably at about room temperature to 150° C. and is complete in about1-15 hours. ##STR44## (wherein R¹ is the same as defined above).

The reaction for converting the compound (14) into the compound (3b) canbe conducted in an appropriate solvent in the presence of a sulfurizingagent.

The solvent can be any of those used in the reaction between thecompound (2) and the compound (4) in the reaction scheme 2.

The sulfurizing agent can be exemplified by phosphorus pentasulfide andLawesson's Reagent.

The proper amount of the sulfurizing agent used is ordinarily 1-10moles, preferably 1-2 moles per 1 mole of the compound (14).

The reaction is conducted ordinarily at room temperature to 150° C.,preferably at about room temperature to 100° C. and is complete in about10 minutes to 5 hours.

When in general formula (1), R¹ or R³ is a 5- to 15- memberedmonocyclic, bicyclic or tricyclic heterocyclic residual group having atleast one tertiary nitrogen atom, the compound (1) can be converted, byoxidation, into a corresponding compound where the at least one nitrogenatom of said heterocyclic residual group is converted into an oxide form(N→O). Also, when in general formula (1), R¹ or R³ is a phenyl grouphaving at least one lower alkylthio group, the phenyl group can beconverted, by the oxidation under the same conditions, into a phenylgroup having at least one lower alkylsulfinyl group or at least onelower alkylsulfonyl group.

When the compound (1) has both of the above two groups (the 5- to15-membered monocyclic, bicyclic or tricyclic heterocyclic residualgroup having at least one tertiary nitrogen atom and the phenyl grouphaving at least one lower alkylthio group), then it is possible that thetwo groups be oxidized simultaneously under the above oxidationconditions. The oxidation product can be easily separated.

These oxidation reactions can be conducted in an appropriate solvent inthe presence of an oxidizing agent. The solvent can be exemplified bywater, organic acids (e.g. formic acid, acetic acid, trifluoroaceticacid), alcohols (e.g. methanol, ethanol), halogenated hydrocarbons (e.g.chloroform, dichloromethane) and mixed solvents thereof. As to theoxidizing agent there can be mentioned, for example, peracids (e.g.performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoicacid, m-chloroperbenzoic acid, o-carbonylperbenzoic acid), hydrogenperoxide, sodium metaperiodate, bichromic acid, bichromates (e.g. sodiumbichromate, potassium bichromate), permanganic acid and permanganates(e.g. potassium permanganate, sodium permanganate).

The proper amount of the oxidizing agent used is ordinarily at least 1mole, preferably 1-2 moles per 1 mole of the starting material. Thereaction is conducted ordinarily at 0°-40° C., preferably at about 0° C.to room temperature and is completed in about 1-15 hours.

When in general formula (1), R¹ or R³ is a 5- to 15-membered monocyclic,bicyclic or tricyclic heterocyclic residual group having at least oneN-oxide group, the heterocyclic residual group can be converted into a5- to 15- membered monocyclic, bicyclic or tricyclic heterocyclicresidual group having at least one oxo group, by a reaction in ahigh-boiling solvent (e.g. tetralin, diphenyl ether, diethylene glycoldimethyl ether or acetic anhydride), ordinarily at 100°-250° C.,preferably at about 100°-200° C. for about 1-10 hours.

When in general formula (1), R¹ or R³ is a 5- to 15-membered monocyclic,bicyclic or tricyclic heterocyclic residual group having at least oneoxo group adjacent to the nitrogen atom of the heterocyclic ring, thecompound (1) can be converted, by reduction, into a correspondingcompound where said at least one oxo group is converted into a methylenegroup.

The reduction can be conducted by, for example, catalytic hydrogenationin an appropriate solvent in the presence of a catalyst. As to thesolvent, there can be mentioned, for example, water, acetic acid,alcohols (e.g. methanol, ethanol, isopropanol), hydrocarbons (e.g.hexane, cyclohexane), ethers (e.g. diethylene glycol dimethyl ether,dioxane, tetrahydrofuran, diethyl ether), esters (e.g. ethyl acetate,methyl acetate), aprotic polar solvents (e.g. dimethylformamide) andmixed solvents thereof. As to the catalyst, there can be used, forexample, palladium, palladium black, palladium-carbon, platinum,platinum oxide, copper chromite and Raney nickel. The proper amount ofthe catalyst used is generally about 0.02-1 time the weight of thestarting material. Desirably, the reaction temperature is ordinarilyabout -20° C. to 100° C., preferably about 0°-70° C. and the hydrogenpressure is ordinarily 1-10 atm. The reaction is complete generally inabout 0.5-20 hours. The reduction may be conducted by catalytichydrogenation, but can be conducted preferably by a method using ahydride reducing agent. As the hydride reducing agent, there can bementioned, for example, lithium aluminum hydride, sodium boron hydrideand diborane. The amount of the hydride reducing agent used isordinarily at least 1 mole, preferably 1-15 moles per 1 mole of thestarting compound. The reduction reaction is conducted ordinarily atabout -60° C. to 150° C., preferably at -30° C. to 100° C. for about 10minutes to 10 hours, ordinarily using an appropriate solvent, forexample, water, a lower alcohol (e.g. methanol, ethanol, isopropanol),an ether (e.g. tetrahydrofuran, diethyl ether, diisopropyl ether,diglyme) or a mixture thereof. The use of an anhydrous solvent such asdiethyl ether, diisopropyl ether, tetrahydrofuran, diglyme or the likeis preferred when the reducing agent used is lithium aluminum hydride ordiborane.

When in the compound (1), R¹ or R³ is a phenyl group having at least onelower alkoxy group or at least one lower alkoxy-substituted lower alkoxygroup, the phenyl group can be converted into a phenyl group having atleast one hydroxyl group, by a dealkylation reaction or adealkoxyalkylation reaction.

The dealkylation reaction is conducted by treating the compound (1) inthe presence of a catalytic reduction catalyst (e.g. palladium-carbon,palladium black) at about 0°-100° C. at a hydrogen pressure of 1-10 atm.for about 0.5-3 hours in an appropriate solvent, for example, water, alower alcohol (e.g. methanol, ethanol, isopropanol), an ether (e.g.dioxane, tetrahydrofuran), acetic acid or a mixed solvent thereof, or byheat-treating the compound (1) at 30°-150° C., preferably 50°-120° C. ina mixture of an acid (e.g. hydrobromic acid, hydrochloric acid) with asolvent (e.g. water, methanol, ethanol, isopropanol), whereby a compound(1) having a hydroxyl group as R¹ or R³ can be derived. A compound (1)having a hydroxyl group as R¹ or R³ can also be obtained by hydrolysis.This hydrolysis is conducted in an appropriate solvent in the presenceof an acid or a basic compound. As to the solvent, there can bementioned, for example, water, lower alcohols (e.g. methanol, ethanol,isopropanol), ethers (e.g. dioxane, tetrahydrofuran), halogenatedhydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride),polar solvents (e.g. acetonitrile), fatty acids (e.g. acetic acid) andmixed solvents thereof. As to the acid, there can be mentioned, forexample, mineral acids (e.g. hydrochloric acid, hydrobromic acid),organic acids (e.g. trifluoroacetic acid), Lewis acids (e.g. borontrifluoride, boron tribromide, aluminum chloride), iodides (e.g. sodiumiodide, potassium iodide) and mixtures between said Lewis acid and saidiodide. As to the basic compound, there can be mentioned, for example,metal hydroxides such as sodium hydroxide, potassium hydroxide, calciumhydroxide and the like. the reaction proceeds favorably ordinarily atroom temperature to 200° C., preferably at room temperature to 150° C.and is completed generally in about 0.5-50 hours.

When in the compound (1), R¹ or R³ is a phenyl group having at least onehydroxyl group, the phenyl group can be converted into a phenyl grouphaving at least one lower alkoxy group or at least one loweralkoxy-substituted lower alkoxy group, by an alkylation reaction. Thealkylation reaction can be conducted, for example, by reacting thecompound (1) with an alkylating agent such as a dialkyl sulfate (e.g.dimethyl sulfate), diazomethane or a compound represented by the generalformula,

    R.sup.5 Y (15)

(wherein R⁵ is a lower alkyl group or a lower alkoxy-substituted loweralkyl group and Y represents a halogen atom) in an appropriate solventin the presence of a basic compound. The solvent can be exemplified byalcohols such as methanol, ethanol, propanol and the like; ethers suchas diethyl ether, tetrahydrofuran, dioxane, ethylene glycol monomethylether and the like; aromatic hydrocarbons such as benzene, toluene,xylene and the like; esters such as methyl acetate, ethyl acetate andthe like; ketones such as acetone, methyl ethyl ketone and the like;polar solvents such as acetonitrile, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide and the like; and mixedsolvents thereof. The basic compound can be exemplified by inorganicbases such as sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium hydride and the like; alkali metals such asmetallic sodium, metallic potassium and the like; alkali metalalcoholates such as sodium ethylate, sodium ethylate and the like; andorganic bases such as triethylamine, pyridine, N,N-dimethylaniline,N-methylmorpholine, 4-methylaminopyridine, DBN, DBU, DABCO and the like.

The proper amount of the alkylating agent used is at least 1 mole,preferably 1-5 moles per 1 mole of the starting compound.

The reaction is conducted ordinarily at 0°-150° C., preferably at aboutroom temperature to 100° C. and is completed in about 0.5-20 hours.

When in the compound (1), R¹ or R³ is a phenyl group having at least onegroup selected from an alkoxycarbonyl group, a lower alkoxy-substitutedlower alkoxycarbonyl group, a lower alkoxycarbonyl-substituted alkenylgroup and a lower alkoxycarbonyl-lower alkyl group, or is a 5- to15-membered monocyclic, bicyclic or tricyclic heterocyclic residualgroup having 1-2 nitrogen, oxygen or sulfur atoms, having at least onelower alkoxycarbonyl group, the R¹ or R³ can be converted, byhydrolysis, into a phenyl group having at least one group selected froma carboxy group, a carboxy-substituted lower alkenyl group and acarboxy-substituted lower alkyl group, or into a 5- to 15-memberedmonocyclic, bicyclic or tricyclic heterocyclic residual group having 1-2nitrogen, oxygen or sulfur atoms, having at least one carboxy group.

The hydrolysis reaction can be conducted under any conditions ordinarilyemployed in hydrolysis. It is specifically conducted in the presence ofa basic compound (e.g. sodium carbonate, potassium carbonate, sodiumhydroxide, potassium hydroxide or barium hydroxide), a mineral acid(e.g. sulfuric acid, hydrochloric acid or nitric acid), an organic acid(e.g. acetic acid or aromatic sulfonic acid) or the like in a solventsuch as water, alcohol (e.g. methanol, ethanol or isopropanol), ketone(e.g. acetone or methyl ethyl ketone), ether (e.g. dioxane or ethyleneglycol dimethyl ether), acetic acid or the like, or in a mixed solventthereof. The reaction proceeds ordinarily at room temperature to 200°C., preferably at about from room temperature to 180° C. and iscompleted generally in about 10 minutes to 30 hours.

When in the compound (1), R¹ or R³ is a phenyl group having at least oneamino group which may have a lower alkyl group or a lower alkanoylgroup, a phenyl group having, as a substituent on the phenyl ring, agroup of the formula ##STR45## wherein R⁸ and R⁹, together with thenitrogen atom being bonded thereto, form a 5- to 6-membered saturatedheterocyclic ring having a secondary nitrogen atom, or a 5- to15-membered monocyclic, bicyclic or tricyclic heterocyclic residualgroup having at least one secondary nitrogen atom, then the R¹ or R³ canbe converted, by an alkylation reaction, into a phenyl group which hasat least one amino group having 1-2 lower alkyl groups or having a loweralkyl group and a lower alkanoyl group, a phenyl group having, as asubstituent on the phenyl ring, a group of the formula ##STR46## whereinR⁸ and R⁹, together with the nitrogen atom being bonded thereto, form a5- to 6-membered saturated heterocyclic ring having a nitrogen atom towhich a lower alkyl group is bonded, or a 5- to 15-membered monocyclic,bicyclic or tricyclic hetero-cyclic residual group having at least onenitrogen atom having a lower alkyl group as a substituent thereon. Whenthe compound (1) has both of the above two groups (the phenyl grouphaving at least one amino group, the 5- to 15-membered monocyclic,bicyclic or tricyclic heterocyclic residual group having at least onesecondary nitrogen atom, or the amino-lower alkyl group), it is possiblethat the two groups be alkylated simultaneously, and the alkylationproduct can be separated easily.

The alkylation reaction is conducted by reacting the compound (1) with acompound represented by the general formula

    R.sup.5 Y                                                  (15)

(wherein R⁵ and Y are the same as defined above) in an appropriate inertsolvent in the presence of a dehydrohalogenating agent.

The inert solvent can be exemplified by halogenated hydrocarbons such asdichloromethane, chloroform and the like; ethers such astetrahydrofuran, diethyl ether and the like; aromatic hydrocarbons suchas benzene, toluene, xylene and the like; esters such as methyl acetate,ethyl acetate and the like; and polar solvents such asdimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide,acetonitrile, acetone, acetic acid, pyridine, water and the like. As thedehydrohalogenating agent, there can be mentioned, for example, organicbases such as triethylamine, trimethylamine, pyridine, dimethylaniline,N-methylmorpholine morpholine, 4-dimethylaminopyridine,4-(1-pyrrolidinyl)pyridine, 1,5-diazabicyclo 4,3,0!nonene-5 (DBN),1,8-diazabicyclo 5,4,0!undecene-7 (DBU), 1,4-diazabicyclo- 2,2,2!octane(DABCO), sodium acetate and the like, as well as inorganic bases such assodium hydride, potassium carbonate, sodium carbonate, potassiumhydrogencarbonate, sodium hydrogencarbonate, potassium hydroxide, sodiumhydroxide and the like. The proper amount of the compound (15) used isordinarily at least 1 mole, preferably 1-3 moles per 1 mole of thestarting material. The reaction is conducted ordinarily at about -20° C.to 150° C., preferably at 0°-100° C. and is completed in about 5 minutesto 15 hours.

When in the compound (1), R¹ or R³ is a phenyl group having at least oneamino group which may have a lower alkyl group, a phenyl group having atleast one hydroxyl group, a 5- to 15-membered monocyclic, bicyclic ortricyclic heterocyclic residual group having at least one secondarynitrogen atom, a phenyl group having, as a substituent on the phenylring, a group of the formula ##STR47## wherein R⁸ and R⁹, together withthe nitrogen atom being bonded thereto, form a 5- to 6-memberedsaturated heterocyclic ring having a secondary nitrogen atom, or aphenyl group having at least one tetrahydropyranyloxy group having, as asubstituent, at least one group selected from a hydroxyl group and ahydroxyl group-substituted lower alkyl group, the R¹ or R³ can beconverted, by a lower alkanoylation reaction, into a phenyl group havingat least one amino group which has a lower alkanoyl group or has a loweralkanoyl group and a lower alkyl group, a phenyl group having at leastone alkanoyloxy group, a 5- to 15-membered monocyclic, bicyclic ortricyclic heterocyclic residual group having at least one nitrogen atomhaving a lower alkanoyl group as a substituent thereon, a phenyl grouphaving, as a substituent on the phenyl ring, a group of the formula##STR48## wherein R⁸ and R⁹, together with the nitrogen atom beingbonded thereto, form a 5- to 6-membered saturated heterocyclic ringhaving a nitrogen atom to which a lower alkanoyl group is bonded, or aphenyl group having at least one tetrahydropyranyloxy group having, as asubstituent, at least one group selected from a lower alkanoyloxy groupand a lower alkanoyloxy group-substituted lower alkyl group. In theabove reaction, when the compound (1) has the above three groups (thephenyl group having at least one amino group which may have a loweralkyl group, the phenyl group having at least one hydroxyl group and the5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclicresidual group having at least one secondary nitrogen atom), it ispossible that all of the three groups be alkanoylated simultaneously,and the alkanoylation product can be separated easily.

The alkanoylation reaction is conducted by reacting the compound (1)with an alkanoylating agent, for example, a compound represented by thegeneral formula,

    R.sup.6 Y                                                  (16)

or

    (R.sup.6).sub.2 O                                          (17)

(wherein R⁶ represents a lower alkanoyl group and Y is the same asabove) in a solventless state or in an appropriate solvent in thepresence or absence, preferably the presence of a basic compound. As tothe appropriate solvent, there can be used, for example, theabove-mentioned aromatic hydrocarbons, lower alcohols (e.g. methanol,ethanol, propanol), DMF, DMSO, halogenated hydrocarbons (e.g.chloroform, methylene chloride), acetone and pyridine. The basiccompound can be exemplified by tertiary amines (e.g. triethylamine,pyridine), sodium hydroxide, potassium hydroxide and sodium hydride. Theproper amount of the lower alkanoylation agent used is at least 1 mole,preferably 1-10 moles per 1 mole of the starting material. The reactionis conducted ordinarily at room temperature to 200° C., preferably atroom temperature to 150° C. and is completed in about 0.5-15 hours.

When in the compound (1), R¹ or R¹ is a 5- to 15-membered monocyclic,bicyclic or tricyclic heterocyclic residual group having at least onesecondary nitrogen atom, the R¹ or R³ can be converted into a 5- to15-membered monocyclic, bicyclic or tricyclic heterocyclic residualgroup having at least one nitrogen atom having a benzoyl group as asubstituent thereon, by reacting the compound (1) with a compoundrepresented by the general formula,

    R.sup.7 Y                                                  (18)

(wherein R⁷ represents a benzoyl group and Y represents a halogen atom).

The reaction can be conducted under the same conditions as employed inthe above alkylation reaction.

When in the compound (1), R¹ or R³ is a phenyl group having at least onecarboxy group or a 5- to 15-membered monocyclic, bicyclic or tricyclicheterocyclic residual group having 1-2 hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom, having at least onecarboxy group, the R¹ or R³ can be converted, by an esterificationreaction, into a phenyl group having at least one alkoxycarbonyl groupor at least one phenyl-lower alkoxycarbonyl group, or a 5- to15-membered monocyclic, bicyclic or tricyclic heterocyclic residualgroup having 1-2 hetero atoms selected from a nitrogen atom, an oxygenatom and a sulfur atom, having at least one lower alkoxycarbonyl group.

The esterification reaction can be conducted by reacting the compound(1) with an alcohol such as methyl alcohol, ethyl alcohol, isopropylalcohol, benzyl alcohol or the like, in the presence of a mineral acid(e.g. hydrochloric acid, sulfuric acid) and a halogenating agent (e.g.thionyl chloride, phosphorus oxychloride, phosphorus pentachloride,phosphorus trichloride) ordinarily at 0°-150° C., preferably at 50°-100°C. for about 1-10 hours.

When in the compound (1), R¹ or R³ is a phenyl group having a hydroxylgroup and an amino group, the hydroxyl group and the amino group beingadjacent to each other, the compound (1) can be converted into acompound (1) where R¹ or R³ is benzoxazol-2-one, by reacting the formercompound (1) with phosgene in an appropriate solvent in the presence ofa basic compound. The basic compound and the solvent can each be any ofthose used in the reaction between the compound (2) and the compound (4)in the Reaction scheme-2.

The reaction is conducted ordinarily at 0°-100° C., preferably at about0°-70° C. and is complete in about 1-5 hours.

A compound (1) where R¹ or R³ is a phenyl group having at least oneamide group which may have a lower alkyl group as a substituent, can beobtained by reacting a compound (1) where R¹ or R³ is a phenyl groupwhich may have at least one carboxy group, with an amine which may havea lower alkyl group as a substituent, under the same conditions asemployed in the amide bonding formation reaction in the reaction scheme3.

A compound (1) where R¹ or R³ is a benzoyl group which may have a loweralkoxy group as a substituent on the phenyl ring, when reduced by thesame reduction using a hydride reducing agent as employed for thecompound where R¹ or R³ is a 5- to 15-membered monocyclic, bicyclic ortricyclic heterocyclic residual group having at least one oxo groupadjacent to the nitrogen atom of the heterocyclic ring, can be convertedinto a compound (1) where R¹ or R³ is a phenyl-lower alkyl group whichmay have a lower alkoxy group as a substituent on the phenyl ring andwhich has a hydroxyl group as a substituent on the lower alkyl group.

A compound (1) where R¹ or R³ is a benzyl group which may have a loweralkoxy group as a substituent on the phenyl ring, when oxidized underthe same conditions as employed for the compound where R¹ or R³ is a 5-to 15-membered monocyclic, bicyclic or tricyclic heterocyclic residualgroup having at least one tertiary nitrogen atom, except that thereaction temperature is changed to ordinarily room temperature to 200°C., preferably room temperature to 150° C., can be converted into acompound (1) where R¹ or R³ is a benzoyl group which may have a loweralkoxy group as a substituent on the phenyl ring. ##STR49## wherein R¹,R², R⁸, R⁹ and X are the same as defined above; R¹⁰ represents an alkoxygroup, a tri-lower alkyl group-substituted silyloxy group, a lower alkylgroup, a hydroxyl group, a lower alkenyloxy group, a lower alkylthiogroup, a phenyl group which may have a group selected from the groupconsisting of a thiazolyl group which may have, as a substituent on thethiazolyl group, a phenyl group which may have a lower alkoxy group onthe phenyl ring, a carboxy group and a hydroxyl group, a loweralkylsulfinyl group, a lower alkylsulfonyl group, a halogen atom, anitro group, a group of the formula, ##STR50## (wherein A, l, R⁸ and R⁹are the same as above), a lower alkanoyl group, a lower alkanoyloxygroup, an alkoxycarbonyl group, a cyano group, a tetrahydropyranyloxygroup which may have 1-4 substituents selected from the group consistingof a hydroxyl group, a lower alkoxycarbonyl group, a phenyl-lower alkoxygroup, a hydroxyl group- or lower alkanoyloxy group-substituted loweralkyl group and a lower alkanoyloxy group, an amidino group, ahydroxysulfonyloxy group, a lower alkoxycarbonyl-substituted loweralkoxy group, a carboxy-substituted lower alkoxy group, a mercaptogroup, a lower alkoxy-substituted lower alkoxy group, a lower alkylgroup having hydroxyl groups, a lower alkenyl group, anaminothiocarbonyloxy group which may have a lower alkyl group as asubstituent, an aminocarbonylthio group which may have a lower alkylgroup as a substituent, a lower alkanoyl-substituted lower alkyl group,a carboxy group, an amino-lower alkoxycarbonyl group which may have alower alkyl group as a substituent, a group of the formula, ##STR51##(R²¹ and R²², which may be the same or different, each represent ahydrogen atom or a lower alkyl group), a phenyl-lower alkoxycarbonylgroup, a cycloalkyl group, a lower alkynyl group, a loweralkoxycarbonyl-substituted lower alkyl group, a carboxy-substitutedalkyl group, a lower alkoxycarbonyl-substituted lower alkenyl group, acarboxy-substituted lower alkenyl group, an amino-lower alkoxy groupwhich may have a lower alkyI group as a substituent, an amino-loweralkoxy-substituted lower alkyl group which may have a lower alkyl groupas a substituent, an amino-lower alkoxycarbonyl-substituted lower alkylgroup which may have a lower alkyl group as a substituent, a loweralkylsulfonyloxy group which may have a halogen atom, or a loweralkoxy-substituted lower alkoxycarbonyl group) m and m' are eachrepresent 0 or an integer of 1-3.!

The reaction between the compound (1c) and the compound (19) can beconducted by, for example,

1 a method (Mannich reaction) wherein the compound (1c) is reacted with##STR52## (R⁸ and R⁹ are the same as defined above) and formaldehyde, or

2 a method wherein the compound (1c) is reacted with a compound (20),##STR53##

The method 1 is conducted by reacting the compound (1c), the compound(19) and formaldehyde in an appropriate solvent in the presence orabsence of an acid. The solvent can be any of those ordinarily used inthe Mannich reaction, and can be exemplified by water, alcohols (e.g.methanol, ethanol, isopropanol), alkanoic acids (e.g. acetic acid,propionic acid), acid anhydrides (e.g. acetic anhydride), plar solvents(e.g. acetone, dimethylformamide) and mixed solvents thereof. The acidcan be exemplified by mineral acids (e.g. hydrochloric acid, hydrobromicacid) and organic acids (e.g. acetic acid). As the formaldehyde, thereare ordinarily used an aqueous solution containing 20-40% by weight offormaldehyde, a formaldehyde trimer, a formaldehyde polymer(paraformaldehyde), etc. The proper amount of the compound (19) used isordinarily at least 1 mole, preferably 1-5 moles per 1 mole of thecompound (1c). The proper amount of formaldehyde used is at least 1 moleper 1 mole of the compound (1c) and ordinarily a large excess relativeto the compound (1c). The reaction proceeds ordinarily at 0°-200° C.,preferably at about room temperature to 150° C. and is completed inabout 0.5-10 hours.

The method 2 is conducted by carrying out the reaction in the presenceof an acid in an appropriate solvent or without solvent. The acid can beexemplifed by mineral acids (e.g. hydrochloric acid, hydrobromic acid,sulfuric acid) and organic acids (e.g. acetic acid, acetic anhydride),preferably acetic anhydride. The solvent can be any of those used in themethod 1. The proper amount of the compound (20) used is ordinarily atleast 1 mole, preferably 1-5 moles per 1 mole of the compound (1c). Thereaction is conducted ordinarily at 0°-150° C., preferably at about roomtemperature to 100° C. and is completed in about 0.5-5 hours.

In said reaction, when R¹ represents a group of the formula, ##STR54##there may also be formed, in some cases, a reaction product between thegroup of R' in compound (1c) with compound (19) or the compound (20),and such product, can easily be separated from the reaction mixture.##STR55## (wherein R², R³, R⁸, R⁹, R¹⁰, m, m' and X are the same asdefined above).

The reaction for converting the compound (1c') into a compound (1d') canbe conducted under the same conditions as employed in the reaction forconvering the compound (1c) into a compound (1d) in the Reactionscheme-8.

In said reaction, when R³ represents a group of the formula, ##STR56##there may also be formed, in some cases, a reaction product of the groupof R³ in compound (1c') with compound (19) or the compound (20), andsuch product, can easily be separated from the reaction mixture.##STR57## (wherein R¹, R², R³, R⁹, R¹⁰, and X are the same as definedabove; n represents 0 or an integer of 1-4).

The reaction between the compound (1e) and the compound (19) and thereaction between the compound (1e') and the compound (19) can beconducted under the same conditions as employed in the reaction betweenthe compound (6) and the compound (4) in the Reaction scheme-3.##STR58## (wherein R¹, R², R³, R⁸, R⁹, R¹⁰, n and X are the same asdefined above).

The reaction for converting the compound (1 f) into a compound (1g) andthe reaction for converting the compound (1f') into a compound (1g') canbe conducted under the same conditions as employed in theabove-mentioned reduction reaction for the compound (1) where R¹ or R³is a 5- to 15- membered monocyclic, bicyclic or tricyclic heterocyclicresidual group having at least one oxo group adjacent to the nitrogenatom of the heterocyclic ring. ##STR59## (wherein R¹, R², R⁸, R⁹, R¹⁰, Xand n are the same as defined above; Y^(a) represents a halogen atom ora lower alkylsulfonyloxy group which may have a halogen atom).

The reaction between the compound (1h) and the compound (19) and thereaction between the compound (1h') and the compound (19) are conductedin an appropriate inert solvent in the presence or absence of a basiccompound. The inert solvent can be exemplified by halogenatedhydrocarbons such as dichloromethane, chloroform and the like; etherssuch as tetrahydrofuran, diethyl ether and the like; aromatichydrocarbons such as benzene, toluene, xylene and the like; esters suchas methyl acetate, ethyl acetate and the like; and polar solvents suchas dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide,acetonitrile, acetone, acetic acid, pyridine, water and the like. As tothe basic compound, there can be mentioned, for example, organic basessuch as triethylamine, trimethylamine, pyridine, dimethylaniline,N-methylmorpholine, 4-dimethylaminopyridine, 4-(1-pyrrolidinyl)pyridine,1,5-diazabicyclo 4,3,0!nonene-5 (DBN), 1,8-diazabicyclo-5,4,0!undecene-7 (DBU), 1,4-diazabicyclo{2,2,2!octane (DABCO), sodiumacetate and the like; and inorganic bases such as sodium hydride,potassium carbonate, sodium carbonate, potassium hydrogencarbonate,sodium hydrogencarbonate, potassium hydroxide, sodium hydroxide and thelike. The proper amount of the compound (19) used is ordinarily at least1 mole, preferably 1-3 moles per 1 mole of the compound (1h) or thecompound (1h'). The reaction is conducted ordinarily at about -20° C. to180° C., preferably at 0°-150° C. and is completed in about 5 minutes to15 hours. The reaction proceeds favorably when a catalyst such as copperpowder or the like is added. ##STR60## (wherein R¹ and X are the same asdefined above; R^(10a) and R¹¹ each represent a lower alkoxycarbonylgroup).

The reaction between the compound (ij) and the compound (21) isconducted in an appropriate solvent in a sealed tube. The solvent can beany of those used in the reaction between the compound (2) and thecompound (3) in the Reaction scheme-1. The proper amount of the compound(21) used is at least 1 mole per 1 mole of the compound (lj) and isordinarily a large excess relative to the compound (lj). The reaction isconducted ordinarily at 50°-200° C., preferably at about 50°-150° C. andis completed in about 10-50 hours. ##STR61## (wherein R¹, R², R³, R⁸,R⁹, R¹⁰, X, n and Y are the same as defined above; A' represents a loweralkylene group).

The reaction between the compound (1l) and the compound (19) and thereaction between the compound (1l') and the compound (19) are conductedin an appropriate inert solvent in the presence of a dehydrohalogenatingagent. The inert solvent can be exemplified by halogenated hydrocarbonssuch as dichloromethane, chloroform and the like; ethers such astetrahydrofuran, diethyl ether and the like; aromatic hydrocarbons suchas benzene, toluene, xylene and the like; esters such as methyl acetate,ethyl acetate and the like; polar solvents such as dimethylformamide,dimethyl sulfoxide, hexamethylphosphoric triamide, acetonitrile,acetone, acetic acid, pyridine, water and the like; and mixed solventsthereof. As to the dehydrohalogenating agent, there can be mentioned,for example, organic bases such as triethylamine, trimethylamine,pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine,4-(1-pyrrolidinyl)pyridine, 1,5-diazabicyclo 4,3,0!nonene-5 (DBN),1,8-diazabicyclo 5,4,0!undecene-7 (DBU), 1,4-diazabicyclo- 2,2,2!octane(DABCO), sodium acetate and the like; and inorganic bases such as sodiumhydride, potassium carbonate, sodium carbonate, potassiumhydrogencarbonate, sodium hydrogencarbonate, potassium hydroxide, sodiumhydroxide and the like. The proper amount of the compound (19) used isordinarily at least 1 mole, preferably 1-3 moles per 1 mole of thecompound (1l) or the compound (1l'). The reaction is conductedordinarily at about -20° C. to 150° C. preferably at 0°-100° C. and iscompleted in about 5 minutes to 20 hours. ##STR62## (wherein R¹, R², Xand Y are the same as defined above; R¹² represents a phenyl group whichmay have a lower alkoxy group as a substituent on the phenyl ring).

The reaction between the compound (1n) and the compound (22) and thereaction between the compound (1n') and the compound (22) can beconducted in an appropriate solvent generally at -70° C. to roomtemperature, preferably at about -30° C. to room temperature for 1-6hours. The solvent can be exemplified by ethers such as diethyl ether,dioxane, tetrahydrofuran and the like; aromatic hydrocarbons such asbenzene, toluene and the like; and saturated hydrocarbons such ashexane, heptane, pentane, cyclohexane and the like. The proper amount ofthe compound (22) used is at least 1 mole, preferably 1-2 moles per 1mole of the compound (1n) or the compound (1n'). The reaction forconverting the compound (1o) into a compound (1p) and the reaction forconverting the compound (1o') into a compound (1p') are conducted in anappropriate solvent in the presence of an oxidizing agent. The oxidizingagent can be exemplified by DDQ, pyridinium chromates (e.g. pyridiniumchlorochromate, pyridinium dichlorochromate), dimethyl sulfoxide-oxalylchloride, bichromic acid, bichromates (e.g. sodium bichromate, potassiumbichromate), permanganic acid, and permanganates (e.g. potassiumpermanganate, sodium permanganate). The solvent can be exemplified bywater; organic acids such as formic acid, acetic acid, trifluoroaceticacid and the like; alcohols such as methanol, ethanol and the like;halogenated hydrocarbons such as chloroform, dichloromethane and thelike; ethers such as tetrahydrofuran, diethyl ether, dioxane and thelike; dimethyl sulfoxide; dimethylformamide; and mixed solvents thereof.Desirably, the oxidizing agent is ordinarily used in a large excessrelative to the starting material. The reaction is conducted ordinarilyat about 0°-150°, preferably at about 0°-100° C. and is completed inabout 1-7 hours. ##STR63## (wherein R¹, R², R³ and X are the same asdefined above; R¹³, R¹⁴ and R¹⁵ are each represents a phenyl group or alower alkyl group; R¹⁶ represents a phenyl-lower alkyl group which mayhave a lower alkyl group as a substituent on the phenyl ring).

The reaction between the compound (1n) and the compound (23) and thereaction between the compound (1n') and the compound (23) are each aso-called Witting reaction. The reaction is conducted in a solvent inthe presence of a basic compound. The basic compound can be exemplifiedby inorganic bases such as metallic sodium, metallic potassium, sodiumhydride, sodium amide, sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydrogencarbonate and the like;metal alcoholates such as potassium ter-butoxide, sodium methylate,sodium ethylate and the like; lithium salts such as methyllithium,n-butyllithium, phenyllithium and the like; and organic bases such aspyridine, piperidine, quinoline, triethylamine, N,N-dimethylaniline andthe like. The solvent can be any as long as it gives no adverse effectto the reaction, and there can be mentioned, for example, ethers (e.g.diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme), armatichydrocarbons (e.g. benzene, toluene, xylene), aliphatic hydrocarbons(e.g. n-hexane, pentane, heptane, cyclohexane), amines (e.g. pyridine,N,N-dimethylaniline) and aprotic polar solvents (e.g. dimethylformamide,dimethyl sulfoxide, hexamethylphosphoric triamide). The proper amount ofthe compound (23) used is ordinarily at least about 1 mole, preferablyabout 1-5 moles per 1 mole of the compound (1n) or the compound (1n').The proper reaction temperature is ordinarily about -70° C. to 150° C.,preferably about -50° C. to 120° C. The reaction is complete generallyin about 0.5-15 hours. ##STR64## (wherein A', Y, R¹, R² and X are thesame as defined above; Y' represents a halogen atom; R¹⁷ represents apiperazinyl group which may have a lower alkyl group as a substituent onthe piperazine ring).

The reaction between the compound (24) and the compound (3) can beconducted under the same conditions as employed for the reaction betweenthe compound (2) and the compound (3) in the above Reaction scheme-1.The reaction between the compound (25) and the compound (26) can beconducted under the same conditions as employed for the reaction betweenthe compound (1l') and the compound (19) in the above Reactionscheme-14. ##STR65## (wherein R¹, R³ and X are the same as definedabove; R¹⁹ and R²⁰ are each the same or different, and are eachrepresents a hydrogen atom or a lower alkyl group).

The reaction between the compound (1s) and the compound (30) can beconducted by, for example, 1 a method wherein the compound (1s) isreacted with ##STR66## (R¹⁹ and R²⁰ are the same as defined above) andformaldehyde (i.e., Mannich reaction), or 2 a method wherein thecompound (1s) is reacted with ##STR67## (R¹⁹ are R²⁰ are the same asdefined above).

The method (1) is conducted by reacting the compound (1s), the compound(30) and formaldehyde in an appropriate solvent in the presence orabsence of an acid. The solvent can be any of those ordinarily used inthe Mannich reaction, and can be exemplified by water, alcohols (e.g.methanol, ethanol, isopropanol), alkanoic acids (e.g. acetic acid,propionic acid), acid anhydrides (e.g. acetic anhydride), polar solvents(e.g. acetone, dimethylformamide) and mixed solvents thereof. The acidcan be examplified by mineral acids (e.g. hydrochloric acid, hydrobromicacid) and organic acids (e.g. acetic acid). As the formaldehyde, thereare ordinarily used an aqueous solution containing 20-40% by weight offormaldehyde, a formaldehyde trimer, a formaldehyde polymer(paraformaldehyde), etc. The proper amount of the compound (30) used isordinarily at least 1 mole, preferably 1-5 moles per 1 mole of thecompound (1s). The proper amount of formaldehyde used is at least 1 moleper 1 mole of the compound (1s) and ordinarily a large excess amountrelative to the compound (1s). The reaction proceeds ordinarily at0°-200° C., preferably at about room temperature to 150° C. and iscomplete in about 0.5-10 hours.

The method 2 is conducted by carrying out the reaction in the presenceof an acid in an appropriate solvent or without solvent. The acid can beexemplified by mineral acids (e.g. hydrochloric acid, hydrobromic acid,sulfuric acid) and organic acids (e.g. acetic acid, acetic anhydride).Acetic anhydride is preferred. The solvent can be any of those used inthe method 1. The proper amount of the compound (31) used is ordinarilyat least 1 mole, preferable 1-5 moles per 1 mole of the compound (1s).The reaction is conducted ordinarily at 0°-150° C., preferably at aboutroom temperature to 100° C. and is complete in about 0.5-5 hours.

When in general formula (1), R¹ or R³ is a phenyl group having at leastone nitro group as a substituent on the phenyl ring, then R¹ or R³ canbe converted, by reduction, into a phenyl group having at least oneamino group as a substituent on the phenyl ring. The reduction reactioncan be conducted under the same conditions as employed in theabove-mentioned catalytic reduction reaction for the oxo group adjacentto the nitrogen atom of the heterocyclic ring. The reduction reactioncan also be conducted by using a reducing agent such as mentioned below.As to the reducing agent, there can be mentioned, for example, a mixtureof iron, zinc, tin or stannous chloride with an acid (e.g. acetic acid,hydrochloric acid, sulfuric acid), or a mixture of iron, ferroussulfate, zinc or tin with an alkali metal hydroxide (e.g. sodiumhydroxide), a sulfide (ammonium sulfide), ammonia water, or an ammoniumsalt (e.g. ammonium chloride). The inert solvent can be exemplified bywater, acetic acid, methanol, ethanol and dioxane. The conditions of thereduction reaction can be suitably selected depending upon the type ofthe reducing agent used. For example, when the reducing agent is amixture of stannous chloride with hydrochloric acid, the reaction can beadvantageously conducted at about 0° C. to room temperature for about0.5-10 hours. The amount of the reducing agent used is at least 1 mole,ordinarily 1-10 moles per 1 mole of the starting material.

When in the compound (1), R¹ or R³ is a phenyl group having at least onehydroxyl group as a substituent on the phenyl ring, then R¹ or R³ can beconverted, by reaction with a tetrahydrofuran derivative (27), having atleast one hydroxyl group as substituent(s), into a phenyl group havingat least one substituted- or unsubstituted-tetrahydropyranyloxy group asthe substituent on the phenyl ring. The reaction can be conducted in anappropriate solvent (e.g. tetrahydrofuran, diethyl ether, dioxane) inthe presence of a phosphorus compound (e.g. triphenylphosphine) and anazo compound (e.g. diethyl azocarboxylate) ordinarily at 0°-100° C.,preferably at about 0°-70° C. for about 1-20 hours. The compound (27) isdesirably used in an amount of at least 1 mole, preferably 1-2 moles per1 mole of the strating material.

When in the compound (1), R¹ or R³ is a phenyl group having, assubstituent(s) on the phenyl ring, at least one tetrahydropyranyloxygroup having at least one lower alkanoyloxy group, then R¹ or R³ can beconverted, by hydrolysis, into a phenyl group having, as substituent(s)on the phenyl ring, at least one tetrahydropyranyloxy group having atleast one hydroxyl group. The hydrolysis reaction can be conducted in anappropriate solvent in the presence of a basic compound. The basiccompound can be exemplified by sodium carbonate, potassium carbonate,sodium hydroxide, potassium hydroxide, barium hydroxide and alkali metalalcoholates (e.g. sodium methylate, sodium ethylate). The solvent can beexemplified by water; alcohols such as methanol, ethanol, isopropanoland the like; ethers such as tetrahydrofuran, dioxane, dimethoxyethaneand the like; halogenated hydrocarbons such as chloroform,dichloromethane, carbon tetrachloride and the like; dimethylformamide,dimethyl sulfoxide, hexamethylphosphoric triamide and mixed solventsthereof. The above reaction proceeds ordinarily at about 0°-200° C.,preferably at about room temperature to 150° C. and is completegenerally in about 0.5-15 hours.

When in the compound (1), R¹ or R³ is a phenyl group having at least onehydroxyl group as a substituent on the phenyl ring, then R¹ or R³ can beconverted, by reaction with a compound of the formula (28),

    YSO.sub.3 H                                                (2s)

(Y is the same as defined above), into a phenyl group having at leastone hydroxysulfonyloxy group as a substituent on the phenyl ring. Thereaction can be conducted under the same conditions as employed in thereaction between the compound (1l) and the compound (19) in the Reactionscheme-14. Preferably, the amount of the compound (28) used isordinarily in a large excess amount relative to the starting material.

When in the compound (1), R¹ or R³ is a phenyl group having at least onehydroxyl as a substituent on the phenyl ring, then R¹ or R³, can beconverted, by reaction with a compound of the formula (29),

    R.sup.18 Y                                                 (29)

(R¹⁸ represents a lower alkoxycarbonyl-substituted lower alkyl group, alower alkenyl group or a thiocarbamoyl group which may have a loweralkyl group as a substituent; and Y is the same as defined above) orwith a compound of the formula (30),

    (R.sup.25 SO.sub.2).sub.2 O                                (30)

(R²⁵ represents a lower alkyl group which may have halogen atoms), intoa phenyl group having, on the phenyl ring, at least one substituentselected from a group of the formula, --OR¹⁸ (R¹⁸ is the same as definedabove) and a group of the formula, R²⁵ SO₂ -- (R²⁵ is the same asdefined above). The reaction can be conducted under the same conditionsas employed in the reaction of the compound (1l) with the compound (19)in the Reaction scheme-14.

When in the compound (1), R¹ or R³ is a phenyl group having at least onelower alkenyloxy group as a substituent on the phenyl ring, then R¹ orR³ can be converted, by the Claisen rearrangement, into a phenyl grouphaving, on the phenyl ring, at least two substituents selected from ahydroxyl group and a lower alkenyl group. The reaction can be conductedby heating in an appropriate solvent. The solvent can be exemplified byone having high-boiling point such as dimethylformamide,tetrahydronaphthalene, o-dichlorobenzene, N,N-dimethylaniline,N,N-diethylaniline and diphenyl ether. The reaction is conductedordinarily at 100°-250° C., preferably at 150°-250° C. and is completedin about 1-30 hours.

When in the compound (1), R¹ or R³ is a phenyl group having, assubstituent(s) on the phenyl ring, a thiocarbamoyloxy group which mayhave a lower alkyl group, then R¹ or R³ can be converted, by heating,into a phenyl group having, as substituent(s on the phenyl ring, atleast one aminocarbonylthio group which may have a lower alkyl group asa substituent. The reaction is conducted in the absence of a solventordinarily at 100°-250° C., preferably at 150°-250° C. and is completedin about 1-10 hours.

When in the compound (1), R¹ or R³ is a phenyl group having, assubstituent(s) on the phenyl ring, at least one aminocarbonylthio groupwhich may have a lower alkyl group, then R¹ or R³ can be converted intoa phenyl group having at least one mercapto group as a substituent onthe phenyl ring, by hydrolysis under the same conditions as employed inthe hydrolysis reaction for the compound (1) where R¹ or R³ is a phenylgroup having at least one lower alkoxycarbonyl group.

When in the compound (1), R¹ or R³ is a phenyl group having at least onenitro group, as substituent(s) on the phenyl ring, then R¹ or R³ can beconverted, by reduction, into a phenyl group having at least one aminogroup, as substituent(s) on the phenyl ring.

The reduction reaction is conducted by, for example, 1 reduction in anappropriate solvent using a catalytic reduction catalyst or 2 reductionin an appropriate inert solvent using, as a reducing agent, for example,a mixture between a metal or a metal salt and an acid, or between ametal or a metal salt and an alkali metal hydroxide, ammonium sulfide orthe like.

In the case 1 using a reduction catalyst, the solvent includes, forexample, water; acetic acid; alcohols such as methanol, ethanol,isopropanol and the like; halogenated hydrocarbons such asdichloromethane, chloroform, dichloroethane and the like; hydrocarbonssuch as hexane, cyclohexane and the like; ethers such as dioxane,tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether and thelike; esters such as ethyl acetate, methyl acetate and the like; aproticpolar solvents such as N,N-dimethylformamide and the like; and mixedsolvents thereof. The catalytic reduction catalyst includes, forexample, palladium, palladium black, palladium-carbon, platinum,platinum oxide, copper chromite and Raney nickel. The proper amount ofthe catalyst used is generally about 0.02-1 time the weight of thestarting material. Desirably, the reaction temperature is ordinarilyabout -20° C. to 150° C., preferably about 0°-100° C. and the reactionpressure is ordinarily 1-10 atom. The reaction is completed generally inabout 0.5-10 hours. An acid such as hydrochloric acid or the like may beadded in the reaction.

In the case 2, there is used, as a reducing agent, a mixture of iron,zinc, tin or stannous chloride with a mineral acid such as hydrochloricacid, sulfuric acid or the like, or a mixture of iron, ferrous sulfate,zinc or tin with an alkali metal hydroxide (e.g. sodium hydride), asulfide (e.g. ammonium sulfide), ammonia water or an ammonium salt (e.g.ammonium chloride). The inert solvent can be exemplified by water,acetic acid, methanol, ethanol and dioxane. The conditions for thereduction reaction can be suitably selected depending upon the type ofthe reducing agent used. For example, when the reducing agent is amixture of stannous chloride with hydrochloric acid, the reaction can beconducted advantageously at about 0° C. to room temperature for about0.5-70 hours. The amount of the reducing agent is at least 1 mole,ordinarily 1-5 moles per 1 mole of the starting material.

When in the compound 91), R¹ or R³ is a phenyl group having at least onelower alkenyl group as a substituent on the phenyl ring, then R¹ or R³can be converted, by oxidation, into a phenyl group having, assubstituent(s) on the phenyl ring, at least one lower alkyl group havingtwo hydroxyl groups.

The reaction can be conducted by reacting the compound (1) with anoxidizing agent in the presence of a co-oxidizing agent in anappropriate solvent.

As to the solvent used in the reaction with an oxidizing agent, therecan be mentioned, for example, ethers such as dioxane, tetrahydrofuran,diethyl ether and the like; aromatic hydrocarbons such as benzene,toluene, xylene and the like; halogenated hydrocarbons such asdichloromethane, dichloroethane, chloroform, carbon tetrachloride andthe like; esters such as ethyl acetate and the like; water; alcoholssuch as methanol, ethanol, isopropanol, tert-butanol and the like; andmixed solvents thereof. The co-oxidizing agent can be exemplified byorganic amine N-oxides such as pyridine N-oxide, N-ethyldiisopropylamineN-oxide, 4-methylmorpholine N-oxide, trimethylamine N-oxide,triethylamine N-oxide and the like. The oxidizing agent can beexemplified by osmium tertoxide. The proper amount of the oxidizingagent used is ordinarily 1 mole, preferably 1-5 moles per 1 mole of thestarting compound. The reaction is conducted at -20° C. to 150° C.,preferably at room temperature to 100° C. and is complete generally inabout 1-15 hours.

When in the compound (1), R¹ or R³ is a phenyl group having at least onelower alkenyl group as substituent(s) on the phenyl ring, then R¹ or R³can be converted, by oxidation, into a phenyl group having, assubstituent(s) on the phenyl ring, at least one lower alkanoylgroup-substituted lower alkyl group or at least one lower alkanoylgroup. The reaction can be conducted in an appropriate solvent in thepresence of an oxidizing agent. As to the solvent, there can bementioned, for example, ethers such as dioxane, tetrahydrofuran, diethylether and the like; aromatic hydrocarbons such as benzene, toluene,xylene and the like; halogenated hydrocarbons such as dichloromethane,dichloroethane, chloroform, carbon tetrachloride and the like; esterssuch as ethyl acetate and the like; water; alcohols such as methanol,ethanol, isopropanol, tert-butanol and the like; and mixed solventsthereof. The oxidizing agent can be exemplified by ozone and osmiumtetroxide-sodium metaperiodate. The reaction is conducted at 20°-150°C., preferably at about 00°-100° C. and is complete generally in about1-20 hours.

When in the compound (1), R¹ or R³ is a phenyl group having at least oneformyl group-substituted lower alkyl group as substituent(s) on thephenyl, then R¹ or R³ can be converted, by reduction, into a phenylgroup having at least one lower alkyl group having hydroxyl groups, assubstituent(s) on the phenyl ring. The reduction can be conducted underthe same conditions as employed in the reduction reaction using ahydride reducing agent, for the compound (1) where R¹ or R³ is a 5- to15-membered monocyclic, bicyclic or tricyclic heterocyclic residualgroup having at least one oxo group adjacent to the nitrogen atom of theheterocyclic ring.

When in the compound (1), R¹ or R³ is a phenyl group having at least onenitrile group or at least one carbamoyl group as substituent(s) on thephenyl ring, or a 5- to 15-membered monocyclic, bicyclic or tricyclicheterocyclic residual group having 1-2 hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom, having at least onenitrile group or at least one carbamoyl group as substituent(s), then R¹or R³ can be converted, by hydrolysis, into a phenyl group having atleast one carboxy group as substituent(s) on the phenyl ring, or a 5- to15-membered monocyclic, bicyclic or tricyclic heterocyclic residualgroup having 1-2 hetero atoms selected from a nitrogen atom, an oxygenatom and a sulfur atom, having at least one carboxyl group assubstituent(s). The hydrolysis reaction can be conducted under the sameconditions as employed in the hydrolysis reaction for the compound 91)where R¹ or R³ is a phenyl group having at least one alkoxycarbonylgroup.

When in the compound (1), R¹ or R³ is a phenyl group having, assubstituent(s) on the phenyl ring, at least one group of the formula,##STR68## (A and l are the same as above; R^(8a) represents a loweralkanoyl group; R^(9a) represents a hydrogen atom, a lower alkyl group,a lower alkanoyl group, an amino-lower alkyl group which may have alower alkyl group as a substituent, or a piperidinyl-lower alkyl group),then R¹ or R³ can be converted, by hydrolysis, into a phenyl grouphaving, as substituent(s) on the phenyl ring, at least one group of theformula,

    --(A).sub.l --NH--R.sup.9a

(A, l and R^(9a) are the same as defined above). The hydrolysis reactioncan be conducted under the same conditions as employed in the hydrolysisreaction for the compound (1) where R¹ or R³ is a phenyl group having atleast one lower alkoxycarbonyl group.

When in the compound (1), R¹ or R³ is a phenyl group having at least onelower alkenyl group as substituent(s) on the phenyl ring, then R¹ or R³can be converted, by reduction, into a phenyl group having at least onelower alkyl group as substituent(s) on the phenyl ring.

The reduction can be conducted under the same conditions as employed inthe reduction reaction by catalytic hydrogenation for the compound (1)where R¹ or R³ is a 5- to 15-membered monocyclic, bicyclic or tricyclicheterocyclic residual group having at least one oxy group adjacent tothe nitrogen atom of mthe heterocyclic ring.

When in the compound 91), R¹ or R³ is a phenyl group having at least onehydroxyl group as substituent(s) on the phenyl ring, then R¹ or R³ canbe converted, by carboxylation, into a phenyl group having at least onehydroxyl group and at least one carboxyl group on the phenyl ring.

The carboxylation reaction can be conducted by reacting the compound (1)with carbon dioxide in the presence of an alkali metal carbonate such aspotassium hydrogencarbonate, potassium carbonate or the like in anappropriate solvent or in the absence of a solvent. The solvent can beexemplified by ehters such as dioxane, tetrahydrofuran, diethyl etherand the like; ketones such as methyl ethyl ketone, acetone and the like;water; pyridine; and glycerine. The reaction is conducted ordinarilyunder 1 to 10 atmospheric pressure at 100°-250° C., preferably at about100°-200° C. and is complete in about 1-20 hours.

When in the compound (1), R¹ or R³ is a substituted or unsubstitutedphenyl group, then R¹ or R³ can be converted, by nitration, into aphenyl group having at least one nitro group on the phenyl ring. Thenitration reaction is conducted under the same conditions as ordinarilyemployed in the nitration for aromatic compounds, for example, by usinga nitrating agent in the absence of or presence of an appropriate inertsolvent. The inert solvent can be exemplified by acetic acid, aceticanhydride and concentrated sulfuric acid. The nitrating agent can beexemplified by fuming nitric acid, concentrated nitric acid, mixed acid(a mixture of sulfuric acid, fuming sulfuric acid, phosphoric acid oracetic anhydride with nitric acid) and a mixture of sulfuric acid-alkalimetal nitrate (e.g. potassium nitrate, sodium nitrate). The properamount of the nitrating agent used is at least 1 mole per 1 mole of thestarting compound and is ordinarily a large excess relative to thestarting compound. The reaction is advantageously conducted at about 0°C. to room temperature for 1-4 hours.

When in the compound (1), R¹ or R³ is a phenyl group having at least onecarboxyl group as substituent(s) on the phenyl ring, then R¹ or R³ canbe converted, by reaction with a compound of the general formula (32),

    R.sup.32 Y                                                 (32)

(R³² represents an alkyl group, a phenyl-lower alkyl group or a loweralkoxy-substituted lower alkyl group), into a phenyl group having atleast one group --COOR³² (R³² is the same as defined above) assubstituent(s) on the phenyl ring. The reaction can be conducted underthe same conditions as employed in the reaction between the compound(1l) and the compound (19) in the Reaction scheme-14.

When in the compound (1), R¹ or R³ is a phenyl group having at least onelower alkenyl group having halogen atoms, as substituent(s) on thephenyl ring, then R¹ or R³ can be converted into a phenyl group havingat least one lower alkynyl group as substituent(s) on the phenyl ring,by a reaction in an appropriate solvent in the presence of a basiccompound.

The solvent can be exemplified by ethers such as diethyl ether, dioxane,tetrahydrofuran, monoglyme, diglyme and the like; aromatic hydrocarbonssuch as benzene, toluene, xylene and the like; and aliphatichydrocarbons such as n-hexane, heptane, cyclohexane and the like. Thebasic compound can be exemplified by alkyl- or aryl-lithium and lithiumamides such as methyllithium, n-butyllithium, phenyllithium lithiumdiisopropylamide and the like.

The reaction temperature is -80° C. to 100° C., preferably at about -80°C. to 70° C. The reaction is completed in about 0.5-15 hours.

When in the compound (1), R¹ or R³ is a phenyl group having at least oneformyl group as substituent(s) on the phenyl ring, then R¹ or R³ can beconverted into a phenyl group having at least one cyano group assubstituent(s) on the phenyl ring, by a reaction withhydroxylamino-O-sulfonic acid in an appropriate solvent. The solvent canbe the same as used in the reaction between the compound (1l) and thecompound (19) in the Reaction scheme-14. The reaction is conductedordinarily at 0°-100° C., preferably at about 0°-70° C. and is completein about 1-10 hours. The proper amount of hydroxylamine-O-sulfonic acidused is at least 1 mole, preferably about 1-2 moles per 1 mole of thestarting material.

When in the compound (1), R¹ or R³ is a phenyl group having at least onehalogen atom as substituent(s) on the phenyl ring, then R¹ or R³ can beconverted, by halogenation, into a phenyl group having at least onehydroxyl group as substituent(s) on the phenyl ring.

The reaction can be conducted by a reaction with a lower alkylsiloxanesuch as hexamethyldisolxane or the like in an appropriate solvent in thepresence of a basic compound.

The solvent can be exemplified by ethers such as diethyl ether, dioxane,tetrahydrofuran, monoglyme, diglyme and the like; aromatic hydrocarbonssuch as benzene, toluene, xylene and the like; and aliphatichydrocarbons such as n-hexane, heptane, cyclohexane and the like. Thebasic compound can be exemplified by alkyl- or aryl-lithium and lithiumamides such as methyllithium, n-butyllithium, phenyllithium, lithiumdiisopropylamide and the like. The reaction temperature is -80° C. to100° C., preferably about -80° C. to 70° C., and the reaction iscomplete in about 0.5-15 hours. The proper amount of the loweralkylsiloxane used is at least 1 mole, preferably about 1-2 moles per 1mole of the starting material.

When in the compound (1), R¹ or R³ is a phenyl group having at least oneformyl group as substituent(s) on the phenyl ring, then R¹ or R³ can beconverted, by oxidation, into a phenyl group having at least one carboxygroup on the phenyl ring.

The reaction can be conducted in an appropriate solvent in the presenceof an oxidizing agent. The solvent can be exemplified by water; alcoholssuch as methanol, ethanol, isopropanol and the like; ketones such asacetone, methyl ethyl ketone and the like; carboxylic acids such asacetic acid, propionic acid and the like; esters such as ethyl acetateand the like; aromatic hydrocarbons such as benzene, chlorobenzene,toluene, xylene and the like; hexamethylphosphoric triamide;dimethylformamide; dimethyl sulfoxide; pyridine; and mixed solventsthereof. As the oxidizing agent, there can be mentioned, for example,per acids (e.g. performic acid, peracetic acid, pertrifluoroacetic acid,perbenzoic acid, m-chloroperbenzoic acid, o-carbonylperbenzoic acid),hydrogen peroxide, sodium metaperiodate, bichromic acid, bichromates(e.g. sodium bichromate, potassium bichromate), permanganic acid,permanganates (e.g. potassium permanganate, sodium permanganate), leadsalts (e.g. lead tetraacetate) and silver oxide. The proper amount ofthe oxidizing agent used is ordinarily at least 1 mole, preferably 1-2moles per 1 mole of the starting material.

The reaction is conducted ordinarily at -10° C. to 100° C., preferablyat about 0°-50° C. and is complete in about 30 minutes to 24 hours.

When in the compound (1), R¹ or R³ is a phenyl group having at least onehydroxyl group as substituent(s) on the phenyl ring, the R¹ or R³ can beconverted into a phenyl group having at least one tri-lower alkylgroup-substituted silyloxy group as substituent(s) on the phenyl ring,by a reaction with a tri-lower alkyl-halogensilane.

The reaction can be conducted in an appropriate solvent in the presenceof a basic compound. The solvent can be any of those used in thereaction between the compound (1l) and the compound (19) in the Reactionscheme 14.

The basic compound can be exemplified by organic bases such as imidazoleand the like. The reaction is conducted ordinarily at -20° C. to 150°C., preferably at 0°-100° C. and is complete in about 5 minutes to 10hours.

The proper amount of the tri-lower alkyl-halogenosilane used is at least1 mole, preferably 1-3 moles per 1 mole of the starting material.##STR69## (wherein R¹, R² and X are the same as above. R²⁶ represents alower alkyl group.)

The reduction of the compound (1u) is preferably conducted by areduction using a hydride reducing agent. As the hydride reducing agent,there can be mentioned, for example, lithium aluminum hydride, sodiumboron hydride and diborane. The amount of the reducing agent used isordinarily at least 1 mole, preferably 1-15 moles per 1 mole of thestarting compound. The reduction reaction is conducted ordinarily atabout -60° C. to 150° C., preferably at -30° C. to 100° C. for about1-20 hours ordinarily in an appropriate solvent such as water, loweralcohol (e.g. methanol, ethanol, isopropanol), ether (e.g.tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme), or mixedsolvent thereof. When lithium aluminum hydride or diborane is used asthe reducing agent, there is preferably used an anhydrous solvent suchas diethyl ether, diisopropyl ether, tetrahydrofuran, diglyme or thelike. ##STR70## {wherein R¹ R² R³ and X are the same as defined aboveR²⁷ represents a group of the formula, ##STR71## (R¹⁰ and n are the sameas defined above; R²⁹ represents a formyl group or an alkoxycarbonylgroup.) or a group of the formula, ##STR72## the group of ##STR73##represents a 5- to 15-membered monocyclic bicyclic or tricyclicheterocyclic residual group having 1-2 hetero atoms selected from anitrogen atom, an oxygen atom and a sulfur atom; R²⁰ may have 1-3substituents selected from the group consisting of an oxo group, analkyl group, a benzoyl group, a lower alkanoyl group, a hydroxyl group,a carboxy group, a lower alkoxycarbonyl group, a lower alkylthio group,a group of the formula, ##STR74## (A is the same as above. R²³ and R²⁴,which may be the same or different, each represent a hydrogen atom or alower alkyl group; R²³ and R²⁴ as well as the nitrogen atom being bondedthereto, together with or without other nitrogen atom or oxygen atom,may form a 5- to 6-membered saturated heterocyclic ring. Theheterocyclic ring may have a lower alkyl group as a substituent.); acyano group, a lower alkyl group having hydroxyl groups, aphenylaminothiocarbonyl group and an amino-lower alkoxycarbonyl groupwhich may have a lower alkyl group as a substituent. R³¹ represents aformyl group or a lower alkoxycarbonyl group. p represents 0 or aninteger of 1 or 2.!R²⁸ represents a group of the formula, ##STR75## (R¹⁰and n are the same as defined above) or a group of the formula,##STR76## (the group of ##STR77## R³⁰ and p are the same as definedabove).}

The reduction of the compound (1x) or the compound (1z) can be conductedunder the same conditions as employed in the reduction conducted using ahydride reducing agent for the compound (1) where R¹ or R³ is a 5- to15-membered monocyclic, bicyclic or tricyclic heterocyclic residualgroup having at least one oxo group adjacent to the nitrogen atom of theheterocyclic ring. ##STR78## wherein R¹, R², R³, X, R³⁰ p and RA are thesame as defined above; R³¹ represents a group of the formula, ##STR79##(R²³ and R²⁴ are the same as defined above) or an amino-lower alkoxygroup which may have a lower alkyl group as a substituent.!

The reaction between the compound (1D) and the compound (31) can beconducted under the same conditions as employed in the reaction betweenthe compound (6) and the compound (4) in the Reaction scheme 3.##STR80## (wherein R¹, R², X, R³⁰, R²³, R²⁴ and RA are the same asdefined above.)

The reduction of the compound (1F) or (1H) can be conducted under thesame conditions as employed in the reduction reaction for the compound(1) where R¹ or R³ is a 5- to 15-membered monocyclic, bicyclic ortricyclic heterocyclic residual group having at least one oxo groupadjacent to the nitrogen atom of the heterocyclic ring. ##STR81##wherein R¹, R², X, p and R³⁰ are the same as, above. R³², R³³ and R³⁴each represent a hydrogen atom or a lower alkyl group. The bond betweenthe 2- and 3-positions in the compound (1K) or (1M) represents a singlebond or a double bond.!

The reaction for converting the compound (1J) or (1L) into a compound(1K) or (1M), respectively, can be conducted in an appropriate solventin the presence of a catalyst. The solvent can be any of those used inthe reaction between the compound (2) and the compound (3) in thereaction scheme 1. The catalyst can be exemplified by metal compoundssuch as Pd(OAc)₂ +Cu(OAc)₂ ·H₂ O and the like, and halides such as KI+I₂and the like. The proper amount of the catalyst used is ordinarily 0.1-1mole per 1 mole of the compound (1J) or (1L). When a halide is used, itis used ordinarily in an amount of 0.005-3 moles per 1 mole of thecompound (1J) or (1L). The reaction is conducted ordinarily at roomtemperature to 250° C., preferably at room temperature to 200° C. and iscomplete ordinarily in about 5-40 hours. When a metal compound is usedas the catalyst, the reaction is preferably conducted in an oxygenatmosphere. When R³² represents a lower alkyl group, the bond betweenthe 2- and 3-positions of the compound (1K) represents a single bond.##STR82## (wherein R¹, R², R³, X and Y are the same as above; R³⁵ andR³⁶ each represent the above-mentioned R³⁰).

The reaction between the compound (1W) and the compound (32) and thereaction between the compound (1P) and the compound (32) can beconducted under the same conditions as employed in the reaction betweenthe compound (2) and the compound (3) in the Reaction scheme 1.##STR83## wherein R¹, R², R³, X, R⁸ and R⁹ are the same as definedabove; R³⁷ represents a group of the formula, ##STR84## (R¹⁰ and n arethe same as defined above) or a group of the formula, ##STR85## (RA, R³⁰and p are the same as defined above); R³⁸ represents a group of theformula, ##STR86## (R¹⁰, R⁸, R⁹ and n are the same as defined above) ora group of the formula, ##STR87## R³⁰, R²³, R²⁴, RA and p are the sameas defined above)!.

In the above reaction, when the R³⁷ of the compound (1R) or (1T)represents a group of the formula, ##STR88## the compound (1R) or (1T)reacts with the compound (19); when the R³⁷ represents a group of theformula, ##STR89## the compound (1R) or (1T) reacts with the compound(33).

The reaction between the compound (1R) or (1T) and the compound (19) or(33) is conducted in the absence of a solvent or in an appropriatesolvent in the presence of a reducing agent. The solvent can beexemplified by water; alcohols such as methanol, ethanol, isopropanoland the like; acetic acid; ethers such as dioxane, tetrahydrofuran,diethyl ether, diglyme and the like; and aromatic hydrocarbons such asbenzene, toluene, xylene and the like. The reduction method can beexemplified by a method using formic acid or a hydride reducing agentsuch as sodium boron hydride, sodium cyanoborohydride, lithium aluminumhydride or the like, and a catalytic reduction method using a catalyticreduction catalyst such as palladium black, palladium-carbon, platinumoxide, platinum black, Raney nickel or the like. When formic acid isused as the reducing agent, the appropriate reaction temperature isordinarily room temperature to 200° C., preferably about 50°-150° C.,and the reaction is complete in about 1-10 hours. The proper amount offormic acid used is a large excess relative to the compound (1R) or(1T). When a hydride reducing agent is used, the appropriate reactiontemperature is ordinarily -30° C. to 100° C., preferably about 0°-70°C., and the reaction is complete in about 30 minutes to 20 hours. Theproper amount of the reducing agent is ordinarily 1-20 moles, preferably1-15 moles per 1 mole of the compound (1R) or (1T). In particular, whenlithium aluminum hydride is used as the reducing agent, it is preferableto use, as a solvent, an ether such as dioxane, tetrahydrofuran, diethylether, diglyme or the like, or an aromatic hydrocarbon such as benzene,toluene, xylene or the like. When a catalytic reduction catalyst isused, the reaction is conducted in a hydrogen atmosphere of ordinarilynormal pressure to 20 atm., preferably normal pressure to 10 atm.ordinarily at -30° C. to 100° C. preferably at 0°-60° C. The properamount of the catalyst used is ordinarily 0.1-40% by weight, preferably1-20% by weight based on the compound (1R) or (1T). The proper amount ofthe compound (19) or (33) used is ordinarily 1 mole per 1 mole of thecompound (1R) or (1T), preferably equimolar to a large excess relativeto the compound (1R) or (1T). ##STR90## (wherein R¹, R², R³, R¹⁰, n andX are the same as above; R³⁹ represents a lower alkanoyl group; R⁴⁰represents a lower alkenyl group, a lower alkoxycarbonyl-substitutedlower alkenyl group, a carboxy-substituted lower alkenyl group or alower alkenyl group having halogen atoms; R⁴¹ represents a lower alkylgroup, a lower alkoxycarbonyl-substituted lower alkyl group or acarboxy-substituted lower alkyl group).

The reaction for converting the compound (1V) or (1Y) into a compound(1W) or (1Z), respectively, is conducted in an appropriate solvent inthe presence of a Witting reagent and a basic compound.

As the Witting reagent, there can be mentioned, for example, phosphoruscompounds represented by the general formula (A),

    (R.sup.42).sub.3 P--CH--R.sup.43 Y.sup.-                   (A)

(wherein R⁴² represents a phenyl group, and R³⁵ represents a lower alkylgroup which may have a lower alkoxycarbonyl group, a carboxyl group or ahalogen atom as a substituent; Y is the same as above), and phosphoruscompounds represented by general formula (B), ##STR91## (wherein R⁴⁴represents a lower alkoxy group; and R⁴⁵ represents a lower alkylgroup). The basic compound can be exemplified by inorganic bases such asmetallic sodium, metallic potassium, sodium hydride, sodium amide,sodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate, sodium hydrogencarbonate and the like; metal alcoholates suchas sodium methylate, sodium ethylate, potassium tert-butoxide and thelike; alkyl- or aryllithiums and lithium amides such as methyllithium,n-butyllithium, phenyllithium, lithium diisopropylamide and the like;and organic bases such as pyridine, piperidine, quinoline,triethylamine, N,N-dimethylaniline and the like. The solvent can be anyas long as it gives no adverse effect on the reaction, and there can bementioned, for example, ethers such as diethyl ether, dioxane,tetrahydrofuran, monoglyme, digyme and the like; aromatic hydrocarbonssuch as benzene, toluene, xylene and the like; aliphatic hydrocarbonssuch as n-hexane, heptane, cyclohexane and the like; aprotic polarsolvents such as pyridine, N,N-dimethylformamide, dimethyl sulfoxide,hexamethylphosphoric triamide and the like; and alcohols such asmethanol, ethanol, isopropanol and the like. The appropriate reactiontemperature is ordinarily -80° C. to 150° C., preferably about -80° C.to 120° C., and the reaction is complete generally in about 0.5-15hours.

When the R⁴⁰ of the compound (1W) or (1Z) is a group other than a loweralkenyl group which have a halogen atom, the reaction for converting thecompound (1W) or (1Z) into a compound (1X) or (1aa), respectively, canbe conducted under the same conditions as employed in the reductionreaction by catalytic hydrogenation for the compound (1) where R¹ or R³is a 5- to 15-membered monocyclic, bicyclic or tricyclic heterocyclicresidual group having at least one oxo group adjacent to the nitrogenatom of the heterocyclic ring. ##STR92## (wherein R¹, R², R³, X, RA, R³⁰and p are the same as above.)

The reaction for converting the compound (1bb) and (1cc) into a compound(1cc) and (1ff), respectively, can be conducted by heating with anilineand sulfur in the absence of a solvent state.

The reaction is conducted ordinarily at 100°-250° C., preferably atabout 100°-200° C., and is complete in about 1-20 hours.

The amounts of aniline and sulfur used are each ordinarily 1-10 moles,preferably 1-2 moles per 1 mole of the compound (1bb) or (1ee). Thereaction for converting the compound (1cc) and (1ff) into a compound(1dd) and (1gg), respectively, can be conducted under the sameconditions as employed in the above-mentioned hydrolysis reaction forthe compound (1) where R^(I) or R³ is a phenyl group having at least onealkoxycarbonyl group.

The products thus obtained in each step can be separated and purified byordinary means. The separation means can be exemplified by solventextraction, dilution, recrystallization, column chromatography andpreparative thin-layer chromatography.

Needless to say, the compounds of the present invention includestereoisomers and optical isomers.

The oxazole derivatives represented by general formula (1) of thepresent invention can be easily converted into acid addition salts byallowing a pharmaceutically acceptable acid to act on said derivatives.The acid addition salts are also included in the present invention. Asthe acid, there can be mentioned, for example, inorganic acids such ashydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid andthe like, as well as organic acids such as acetic acid, oxalic acid,succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid,citric acid, malonic acid, methanesulfonic acid, benzoic acid and thelike.

Of the thiazole or oxazole derivatives represented by general formula(1) of the present invention, those compounds having acidic groups canbe easily converted into respective salts by allowing a pharmceuticallyacceptable basic compound to act on the compounds. As the basiccompound, there can be mentioned, for example, sodium hydroxide,potassium hydroxide, calcium hydroxide, sodium carbonate and potassiumhydrogencarbonate.

The compounds of the present invention are generally used in the form ofordinary pharmaceutical preparations. The pharmaceutical preparationsare prepared using diluents or excipients ordinarily used, such asfiller, bulking agent, binder, humectant, disintegrator, surfactant,lubricant and the like. The pharmaceutical preparations can be used invarious forms depending upon the purpose of remedy, and typical formsinclude tablets, pills, powders, solutions, suspensions, emulsions,granules, capsules, suppositories, injections (solutions, suspensions,etc.), ointments, etc. In preparing tablets, various carriersconventionally known in the art can be used. The carriers can beexemplified by excipients such as lactose, white sugar, sodium chloride,grape sugar, urea, starch, calcium carbonate, kaolin, crystallinecellulose, silicic acid and the like; binders such as water, ethanol,propanol, simple syrup, grape sugar solution, starch solution, gelationsolution, carboxymethyl cellulose, shellac, methyl cellulose, potassiumphosphate, polyvinylpyrrolidone and the like; disintegrators such as drystarch, sodium alginate, powdered agar, powdered laminaran, sodiumhydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan-fattyacid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch,lactose and the like; disintegration inhibitors such as white sugar,stearin, cacao butter, hydrogenated oil and the like; absorptionpromoters such as quaternary ammonium salts, sodium lauryl sulfate andthe like; humectants such as glycerine, starch and the like; adsorbentssuch as starch, lactose, kaolin, bentonite, colloidal silicic acid andthe like; and lubricants such as refined talc, stearic acid salts, boricacid powder, polyethylene glycol and the like. The tablets can beprepared, as necessary, in the form of ordinary coated tablets, such assugar-coated tablets, enteric coated tablets or film-coated tablets, orin the form of double-layered tablets or multi-layered tablets. Inpreparing pills, various carriers conventionally known in the art can beused. The carriers can be exemplified by excipients such as grape sugar,lactose, starch, cacao butter, hardened vegetable oils, kaolin, talc andthe like; binders such as powdered acacia, powdered tragacanth, gelatin,ethanol and the like; and disintegrators such as laminaran, agar and thelike. In preparing suppositories, various carriers conventionally knownin the art can be used. The carriers can be exemplified by apolyethylene glycol, cacao butter, a higher alcohol, a higher alcoholester, gelatin and a semi-synthetic glyceride. In preparing injections(solutions, emulsions, suspensions), they are sterilized and preferablyisotonic to blood. In preparing these solutions, emulsions andsuspensions, there can be used all of the diluents conventionally usedin the art, such as water, aqueous lactic acid solution, ethyl alcohol,propylene glycol, ethoxylated isostearyl alcohol, polyoxyisostearylalcohol and polyoxyethylene sorbitan-fatty acid ester. In this case, theinjections may contain sodium chloride, grape sugar or glycerine in anamount sufficient to make the injections isotonic, and may furthercontain a solubilizing agent, a buffer solution, a soothing agent, etc.all ordinarily used. The pharmaceutical preparations may furthermorecontain, as necessary, a coloring agent, a preservative, a perfume, aflavoring agent, a sweetening agent and other drugs. In preparingpastes, creams and gels, there can be used various diluentsconventionally known in the art, such as white petrolatum, paraffin,glycerine, cellulose derivative, polyethylene glycol, silicon, bentoniteand the like.

The amount of the present compound of general formula (1) or a saltthereof to be contained in a pharmaceutical preparation is notparticularly restricted and can be appropriately selected in a widerange, but preferably is ordinarily 1-70% by weight in thepharmaceutical preparation.

The method for administering the pharmaceutical preparation is notparticularly restricted. The pharmaceutical preparation can beadministered in various methods depending upon the form of preparation,the age, sex and other conditions of patient, the degree of diseasecondition of patient, etc. For example, tablets, pills, a solution, asuspension, an emulsion, granules or capsules are administered orally.An injection is intravenously administered singly or in admixture withan ordinary auxiliary solution of grape sugar, amino acid or the like,or, as necessary, is singly administered intramuscularly, intradermally,subcutaneously or intraperitoneally. Suppositories are administeredintrarectally.

The dose of the pharmaceutical preparation of the present invention isappropriately selected depending upon the administration method, theage, sex and other conditions of patient, the degree of diseasecondition of patient, etc., but preferably is ordinarily about 0.2-200mg per kg of body weight per day in terms of the amount of the activeingredient, i.e. the present compound (1).

EXAMPLES

The present invention is hereinafter described with reference toReference Examples, Examples, Preparation Examples and PharmacologicalTests.

Reference Example 1

25 g of 3,4-dimethoxybenzonitrile and 23 g of thioacetamide weredissolved in 120 ml of 10% hydrochloric acid-DMF. The solution washeated at 90° C. for 3 hours. The solution was further heated at 130° C.for 5 hours to conduct a reaction. The solvent was removed bydistillation. The residue was washed twice with 100 ml of diethyl ether.Similar washing was conducted with 100 ml of water. The resultingcrystals were collected by filtration and dried. Recrystallization frommethanol was conducted to obtain 18.7 g of 3,4-dimethoxythiobenzamide aslight brown columnar crystals.

M-P-: 170°-175° C. (decomposed)

NMR (CDC"3) δ:

3.94 (3H, s)

3.95 (3H, s)

6.83 (1H, d, J=8.4Hz),

7.15 (1H, brs),

7.38 (1H, dd, J=2.2Hz, 8.4Hz),

7.52 (1H, brs),

7.63 (1H, d, J=2.2Hz).

Reference Example 2

500 mg of 3,4,5-trimethoxybenzamide was suspended in 15 ml of benzene.Thereto was added 526 mg of phosphorus pentasulfide. The mixture wasrefluxed for 30 minutes with heating. The solvent was removed bydistillation. To the residue were added 5 ml of 10% sodium hydroxide and5 ml of water. The mixture was stirred for 30 minutes. The reactionmixture was filtered, and the resulting solid was washed with smallamounts of water and ethanol and dried to obtain 330 mg of3,4,5-trimethoxythiobenzamide as a yellow powder.

M.p.: 182.5°-184° C.

Reference Example 3

4 g of 3',5'-diacetyloxyacetophenone was suspended in 75 ml of carbondisulfide. Thereto was dropwise added a solution of 0.90 ml of brominedissolved in 25 ml of carbon disulfide, at room temperature in about 1hour. The system was heated to about 50° C. ocassionally in the courseof dropwise addition and, each time when a reaction started, the systemwas returned to room temperature and stirred. After the completion ofthe dropwise addition, stirring was conducted at room temperature for 1hour. After the completion of the reaction, the solvent was removed bydistillation to obtain 5.53 g of 3',5'-diacetyloxy-2-bromoacetophenoneas brown crystals.

M.p.: 61°-62° C.

Reference Example 4

5.47 g of chloroacetyl chloride was dissolved in 20 ml ofdichloromethane. Thereto was added 6.46 g of finely ground aluminumchloride with ice-cooling. Stirring was conducted for 30 minutes.Thereto was added 2 g of 3,4-dihydro-2H-1,4-benzothiazin-3(4H)-one. Themixture was stirred for 4 hours with ice-cooling and then overnight atroom temperature. The reaction mixture was poured into ice water. Theresulting crystals were collected by filtration, water-washed and driedto obtain 3.03 g of6-α-chloroacetyl-3,4-dihydro-2H-1,4-benzothiazin-3-one.

NMR (DNSO-d6) δ:

3.55 (2H, s),

5.10 (2H, s),

7.65-7.45 (3H, m),

10.76 (1H, s).

Reference Example 5

2 g of 3,4-dimethoxybenzoic acid was dissolved in 80 ml of methanol.Thereto was added 600 mg of sodium methoxide. The mixture was stirredfor 30 minutes. The solvent was removed by distillation. The residue wasdissolved in 50 ml of DMF. Thereto was added 2.56 g of6-α-chloroacetyl-3,4-dihydrocarbostyril. The mixture was stirred at 140°C. for 2 hours. The solvent was removed by distillation. Water was addedto the residue. The resulting crystals were collected by filtration anddried to obtain 4.8 g of 6-2-(3,4-dimethoxybenzoyloxy)acetyl!-3,4-dihydrocarbostyril as a whitepowder.

M.p.: 215°-216° C.

Reference Example 6

3 g of 6-α-aminoacetyl-3,4-dihydrocarbostyril monohydrochloride wassuspended in 60 ml of tetrahydrofuran. Thereto were added 7 ml oftriethylamine and 2.8 mg of 3,4-dimethoxybenzoyl chloride. The mixturewas stirred at room temperature. After 3 hours, the resulting crystalswere collected by filtration, methanol-washed and dried to obtain 2.6 gof 6- 2-(3,4-dimethoxybenzoylamino)acetyl!-3,4-dihydrocarbostyril asWhite acicular crystals.

M.p.: 246°-247° C.

Reference Examples 7-38

Compounds shown in Table 1 were obtained by using respective startingmaterials, in the same procedure as in Reference Example 1 or 2.

                  TABLE 1                                                         ______________________________________                                         ##STR93##                                                                    Refer-                                                                        ence                                                                          Exam-                                                                         ple   R.sup.1            Properties                                           ______________________________________                                               ##STR94##         NMR(DMSO-d.sub.6) δ: 8.62-8.67(1H, m),                                  8.83(1H, d, J-2.6Hz), 9.55(1H, d, J=1.4Hz),                                   10.02(1H, brs), 10.32(1H, brs)                       8                                                                                    ##STR95##         NMR(DMSO-d.sub.6) δ: 7.60(1H, t, J=4.8Hz),                              .89(2H, d, J=4.8Hz), 9.89(1H, brs), 10.30(1H,                                 brs)                                                 9                                                                                    ##STR96##         Crystal form: Light brown acicular (recrystallize                             d from ethanol) Mp: 86-87° C.(HCl salt)       10                                                                                   ##STR97##         NMR(DMSO-d.sub.6) δ: 6.12(2H, s), 6.96(1H,                              d, J=8.2Hz), 7.51(1H, d, J=1.8Hz), 7.59(1H, dd,                               J=1.8Hz, 8.2Hz) , 9.37(1H, brs), 9.73(1H, brs)       11                                                                                   ##STR98##         Crystal form: Yellow columnar (recrystallized                                 from ethyl acetate-n-hexane) Mp: 116-117°                              C.                                                   12                                                                                   ##STR99##         Crystal form: Yellow columnar (recrystallized                                 from ethyl acetate) Mp: 130-131° C.           13                                                                                   ##STR100##        NMR(DMSO-d.sub.6) δ: 3.80(3H, s), 3.84(3H,                              s), 6.50-6.63(2H, m), 8.00-8.10(1H, m), 9.14(1H,                              brs), 9.79(1H, brs)                                  14                                                                                   ##STR101##        Crystal form: Brown plate (recrystallized from                                methanol) Mp: 144-145° C.                     15                                                                                   ##STR102##        Crystal form: Light brown powder (recrystallized                              from ethanol) Mp: 133-134° C.                 16                                                                                   ##STR103##        Crystal form: Brown powder (recrystallized from                               dimethylformamide- ethanol) Mp: 243-246°                               C.                                                   17                                                                                   ##STR104##        Crystal form: Yellow scaly (recrystallized from                               dimethylformamide- water)                            18                                                                                   ##STR105##        NMR(DMSO-d.sub.6) δ: 12.90(1H, brs),                                    11.66(1H, brs), 9.81(1H, brs), 9.39(1H, d,                                    J=7Hz), 8.27(1H, d, J=8Hz), 7.9-7.6(2H, m),                                   7.6-7.4(1H, m)                                       19                                                                                   ##STR106##        NMR(CDCl.sub.3) δ: 7.57(1H, dd, J=5.1Hz,                                1.1Hz), 7.50(1H, dd, J=3.9Hz, 1.1Hz), 7.09(1H,                                dd, J=5.0Hz, 3.9Hz), 7.6-6.9(2H, br)                 20                                                                                   ##STR107##        NMR(CDCl.sub.3) δ: 8.00(1H, dd, J=3.0Hz,                                1.4Hz), 7.51(1H, dd, J=5.1Hz, 1.4=Hz), 7.33(1H,                               dd, J=5.1Hz, 3.0Hz), 7.9-7.0(2H, br)                 21                                                                                   ##STR108##        NMR(CDCl.sub.3) δ: 10.0-9.3(1H, br),                                    7.05(1H, brs), 7.1-6.7(2H, br), 6.65(1H, brs),                                6.35-6.25(1H, m)                                     22                                                                                   ##STR109##        NMR(DMSO-d.sub.6) δ: 10.38(1H, brs),                                    10.15(1H, brs), 8.25-8.0(2H, m), 7.7-7.45(2H,                                 m)                                                   23                                                                                   ##STR110##        NMR(CDCl.sub.3) δ: 7.71(1H, d, J=2.1Hz),                                7.6(1H, brs), 7.3(1H, brs), 7.32(1H, dd,                                      J=8.3Hz, 2.1Hz) , 7.27(1H, s), 6.89(1H, d,                                    J=8.3Hz), 6.22(1H, s), 3.97(3H, s)                   24                                                                                   ##STR111##        NMR(CDCl.sub.3) δ: 7.55(1H, dd, J=8.5Hz,                                2.3Hz), 7.5(1H, brs), 7.45(1H, d, J=2.3Hz),                                   7.15(1H, brs), 6.86(1H, d, J=8.5Hz), 5.73(1H,                                 s), 3.95(3H, s)                                      25                                                                                   ##STR112##        NMR(CDCl.sub.3) δ: 8.0-7.85(2H, m),                                     7.55(1H, brs), 7.1(1H, brs), 7.0-6.85(2H, m),                                 3.86(3H, s)                                          26                                                                                   ##STR113##        NMR(DMSO-d.sub.6) δ: 10.22(1H, brs),                                    9.81(1H, brs), 8.24(2H, d, J=8.6Hz), 8.01(2H, d,                              J=8.8Hz)                                             27                                                                                   ##STR114##        NMR(DMSO-d.sub.6) δ: 9.95(1H, brs),                                     9.55(1H, brs), 7.95-7.85(2H, m), 7.55-7.45(2H,                                m)                                                   28                                                                                   ##STR115##        NMR(DMSO-d.sub.6) δ: 10.06(1H, brs),                                    9.67(1H, brs), 8.15-7.85(4H, m), 4.33(2H, dg,                                 J=7.2Hz, 4.0Hz), 1.31(3H, t, J=7.2Hz)                29                                                                                   ##STR116##        NMR(DMSO-d.sub.6) δ: 9.62(1H, brs),                                     9.30(1H, brs), 7.65-7.5(2H, m), 6.95(1H, d,                                   J=9.1Hz), 4.07(2H, q, J=7Hz), 4.04(2H, q,                                     J=7Hz), 1.33(6H, t, J=7Hz)                           30                                                                                   ##STR117##        NMR(DMSO-d.sub.6) δ: 10.05(1H, brs),                                    9.65(1H, brs), 8.02-7.85(4H, m), 2.60(3H, s)         31                                                                                   ##STR118##        NMR(DMSO-d.sub.6) δ: 9.68(1H, brs),                                     9.33(1H, brs), 7.71(1H, d, J=1.7Hz), 7.63(1H, d,                              J=7.8Hz, 1.9Hz), 7.15(1H, d, J=7.9Hz), 2.24(6H,                               s)                                                   32                                                                                   ##STR119##        NMR(DMSO-d.sub.6) δ: 9.88(1H, brs),                                     9.50(1H, brs), 8.05-7.9(2H, m), 7.3-7.15(2H, m)      33                                                                                   ##STR120##        NMR(DMSO-d.sub.6) δ: 9.93(1H, brs),                                     9.54(1H, brs), 7.93(1H, d, J=1.8Hz), 7.77(1H,                                 dd, J=8.0Hz, 1.9Hz), 7.39(1H, d, J=8.0Hz),                                    2.34(3H, s)                                          34                                                                                   ##STR121##        NMR(DMSO-d.sub.6) δ: 10.21(1H, brs),                                    9.85(1H, brs), 8.69(1H, t, J=2Hz), 8.4-8.2(2H,                                m), 7.71(1H, t, J=8Hz)                               35                                                                                   ##STR122##        NMR(DMSO-d.sub.6) δ: 10.09(1H, brs),                                    9.66(1H, brs), 8.08(1H, d, J=2.2Hz), 7.86(1H,                                 dd, J=8.6Hz, 2.2Hz), 7.69(1H, d, J=8.6Hz)            36                                                                                   ##STR123##        NMR(DMSO-d.sub.6) δ: 9.76(1H, brs),                                     9.43(1H, brs), 7.59(1H, dd, J=6.6Hz, 1.4Hz),                                  7.49(1H, d, J=1.3Hz), 7.14(1H, d, J=6.6Hz),                                   3.85(3H, s), 2.41(3H, s)                             37                                                                                   ##STR124##        NMR(DMSO-d.sub.6) δ: 9.95(1H, brs),                                     9.56(1H, brs), 7.9-7.7(2H, m), 7.7-7.5(2H, m)        38                                                                                   ##STR125##        NMR(DMSO-d.sub.6) δ: 9.65(1H, brs),                                     9.32(1H, brs), 7.65-7.5(2H, m), 7.45-7.3(1H, m),                              .15-6.9(1H, m), 6.15-5.9(1H, m), 5.5-5.2(2H, m),                              .8-4.55(2H, m), 3.80(3H, s)                          ______________________________________                                    

Reference Examples 39-60

Compounds shown in Table 3 were obtained by using respective startingmaterials, in the same procedure as in Reference Example 3 or 4.

                                      TABLE 2                                     __________________________________________________________________________     ##STR126##                                                                   Reference                                                                     Example                                                                            R.sup.2                                                                         R.sup.3        Y Properties                                            __________________________________________________________________________    39   H                                                                                ##STR127##    Cl                                                                              Crystal form: White powder (recrystallized from                               acetone) Mp: 210-212° C. (decomposed)          40   H                                                                                ##STR128##    Br                                                                              Crystal form: White powder (recrystallized from                               ethyl acetate-n- hexane) Mp: 85-86° C.         41   H                                                                                ##STR129##    Br                                                                              NMR(CDCl.sub.3) δ: 4.42(2H, s), 8.93(2H,                                s)                                                    42   H                                                                                ##STR130##    Br                                                                              NMR(DMSO-d.sub.6) δ: 12.75(1H, brs),                                    8.64(1H, d, J=6.8Hz), 8.23(1H, d, J=8.1Hz),                                   7.8-7.6(2H, m), 7.55-7.4(1H, m), 4.93(2H, s)          43   H                                                                                ##STR131##    Cl                                                                              NMR(DMSO-d.sub.6) δ: 10.76(1H,                                          s), 7.65--7.45(3H, m), 5.10(2H, s), 3.55(2H, s)       44   H                                                                                ##STR132##    Cl                                                                              NMR(CDCl.sub.3) δ: 2.30(6H, s), 4.65(2H,                                s), 7.64(2H, s)                                       45   H                                                                                ##STR133##    Cl                                                                              NMR(CDCl.sub.3) δ: 1.32(9H, s), 1.42(9H,                                s), 4.75(2H, s), 7.50(1H, d, J=2.4Hz), 7.60(1H,                               d, J=2.4Hz)                                           46   H                                                                                ##STR134##    Cl                                                                              NMR(CDCl.sub.3) δ: 2.53(3H, s), 4.66(2H,                                s), 7.29(1H, d, J=8.8Hz), 7.87(1H, d, J=8.8Hz),       47   H                                                                                ##STR135##    Cl                                                                              NMR(CDCl.sub.3) δ: 1.33(9H, s), 4.30(1H,                                s), 4.76(1H, s), 6.91-7.18(1H, m), 7.34-7.48(1H,                              m), 7.58-7.72(1H, m)                                  48   H                                                                                ##STR136##    Br                                                                              NMR(CDCl.sub.3) δ: 7.89(1H, d, J=8.6Hz),                                7.14(1H, dd, J=8.6Hz, 2.3Hz), 7.05(1H, d,                                     J=2.2Hz), 4.40(2H, s), 2.37(3H, s), 2.32(3H, s)       49   H                                                                                ##STR137##    Cl                                                                              Crystal form: White powder Mp: 189-191°                                C.                                                    50                                                                                    ##STR138##    Br                                                                              Crystal form: Light green acicular (recrystallized                             from methanol) Mp: 151-153° C.                51   H                                                                                ##STR139##    Cl                                                                              Crystal form: Colorless acicular Mp:                                          238-240° C.                                    52   H                                                                                ##STR140##    Cl                                                                              NMR(DMSO-d.sub.6) δ: 5.14(2H, s), 7.06(1H,                              d, J=8.2Hz), 7.52(1H, s), 7.70(1H, dd, J=1.6Hz,                               8.2Hz, 10.97(1H, s), 11.12(1H, s)                     53   H                                                                                ##STR141##    Br                                                                              Crystal form: White powder Mp: 201-210° C.                             (decomposed)                                          54   H                                                                                ##STR142##    Cl                                                                              Crystal form: Colorless plate Mp: 210-215°                             C.                                                    55   H                                                                                ##STR143##    Cl                                                                              Crystal form: Light yellow acicular Mp:                                       179-180° C.                                    56   H                                                                                ##STR144##    Cl                                                                              Crystal form: White powder (recrystallized from                               methanol-chloroform) Mp: 246.5-247° C.         57   H                                                                                ##STR145##    Cl                                                                              Crystal form: White powder Mp: 146-148°                                C.                                                    58   H                                                                                ##STR146##    Cl                                                                              NMR(DMSO-d.sub.6) δ: 2.43-2.56(2H, m),                                  2.93-3.03(2H, m), 5.13(2H, s), 7.35(1H, d,                                    J=6.4Hz), 7.43(1H, d, J=1.4Hz), 7.58(1H, dd,                                  J=1.4Hz, 6.4Hz), 10.28(1H, s)                         59   H                                                                                ##STR147##    Br                                                                              Crystal form: White powder NMR(DMSO-d.sub.6)                                  δ: 4.82(2H, s), 7.18(1H, d, J=8.2Hz),                                   7.90(1H, dd, J=1.8Hz, 8.4Hz), 8.25(1H, d,                                     J=1.8Hz)                                              60   H                                                                                ##STR148##    Br                                                                              Crystal form: Yellow acicular (recrystallized                                 from ethyl acetate-n- hexane) Mp: 83-84°       __________________________________________________________________________                            C.                                                

Reference Example 61

1.5 g of 1,3-dichloroacetone and 2.3 g of 3,4-dimethoxythiobenzamidewere suspended in 100 ml of ethanol. The suspension was heated for 3hours to complete the reaction. The solvent was removed by distillation.The residue was purified by silica gel column chromatography to obtain1.86 g of 2-(3,4-dimethoxyphenyl)-4-chloromethylthiazole as a colorlessviscous oil.

NMR (CDCl₃) δ:

3.94 (3H, s),

3.99 (3H, s),

4.74 (2H, s),

6.90 (1H, d, J=8.3Hz),

7.24 (1H, s),

7.46 (1H, dd, J=2.1Hz, 8.3Hz),

7.53 (1H, d, J=2.1Hz).

Reference Examples 62-70

Compounds shown in Table 3 where obtained by using respective startingmaterials, in the same procedure in Reference Example 1 or 2.

                                      TABLE 3                                     __________________________________________________________________________     ##STR149##                                                                   Reference                                                                     Example                                                                             R.sup.1        Properties                                               __________________________________________________________________________    62                                                                                   ##STR150##    NMR(DMSO-d.sub.6) δ: 0.86(6H, brs),                                     1.10-1.53(28H, m), 1.60-1.8(4H, m), 3.85-4.15(4H,                             m), 6.94(1H, d, J=9.2Hz), 7.53-7.65(2H, m), 9.29(1H,                          brs), 9.61(1H, brs)                                      63                                                                                   ##STR151##    NMR(DMSO-d.sub.6) δ: 0.92(6H, t, J=7.2Hz),                              1.30-1.55(4H, m), 1.55-1.81(4H, m), 3.99(4H, q,                               J=6.2Hz), 6.96(1H, d, J=9.1Hz) 7.50- 7.65(1H, m),                             9.30(1H, brs), 9.62(1H, brs)                             64                                                                                   ##STR152##    NMR(DMSO-d.sub.6) δ: 0.97(6H, t, J=7.4Hz),                              1.58-1.35(4H, m) 3.95(4H, q, J=6.4Hz), 6.96(1H, d,                            J=9.1Hz), 7.50-7.62(2H, m), 9.30(1H, brs), 9.62(1H,                           brs)                                                     65                                                                                   ##STR153##    NMR(DMSO-d.sub.6) δ: 0.96(3H, t, J=7.3Hz),                              1.61-1.86(2H, m), 3.97(3H, s), 3.96(2H, t, J=6.6Hz),                          .96(1H, d, J=9.2Hz), 7.50-7.62(2H, m), 9.32(1H,                               brs), 9.63(1H, brs)                                      66                                                                                   ##STR154##    NMR(DMSO-d.sub.6) δ: 0.92(3H, t, J=7.2Hz),                              1.30-1.55(2H, m), 1.55-1.80(2H, m), 3.78(3H, s),                              4.00(2H, t, J=6.5Hz) , 6.96(1H, d, J-9.1Hz),                                  7.52-7.66(2H, m), 9.31(1H, brs), 9.63(1H, brs)           67                                                                                   ##STR155##    NMR(DMSO-d.sub.6) δ: 1.33(3H, t, J=6.9Hz),                              3.80(3H, s), 4.04(2H, q, J=6.9Hz), 6.96(1H, d,                                J=8.2Hz), 7.50-7.66(2H, m), 9.31(1H, brs), 9.63(1H,                           brs)                                                     68                                                                                   ##STR156##    NMR(DMSO-d.sub.6) δ: 0.97(3H, t, J=7.4Hz),                              1.63-1.88(2H, m), 3.80(3H, s), 3.94(2H, t, J=6.6Hz),                          .96(1H, d, J=8.3Hz), 7.53-7.67(2H, m), 9.31(1H,                               brs), 9.63(1H, brs)                                      69                                                                                   ##STR157##    NMR(DMSO-d.sub.6) δ: 1.33(3H, t, J=7.0Hz),                              3.78(3H, s), 4.05(2H, q, J=7.0Hz), 6.95(1H, d,                                J=9.1Hz), 7.51-7.66(2H, m), 9.31(1H, brs), 9.64(1H,                           brs)                                                     70                                                                                   ##STR158##    NMR(DMSO-.sub.6) δ: 3.77(3H, s), 3.87(3H, s),                           7.58(1H, d, J=2.1Hz), 7.75(1H, d, J=2.1Hz), 9.52                              (1H, brs), 9.95(1H, brs)                                 __________________________________________________________________________

Reference Examples 71-74

Compounds shown in Table 4 were obtained by using respective startingmaterials, in the same procedure as in Reference Example 3 or 4.

                                      TABLE 4                                     __________________________________________________________________________     ##STR159##                                                                   Reference                                                                     Example                                                                            R.sup.2                                                                         R.sup.3         Y Properties                                           __________________________________________________________________________    71                                                                                    ##STR160##     Br                                                                              NMR (CDCl.sub.3) δ: 3.91 (3H, s), 3.96                                  (3H, s), 4.49 (2H, s), 7.66-7.75 (1H, m), 7.75-                               7.86 (1H, m), 8.19 (1H, t, J=1.4Hz)                  72                                                                                    ##STR161##     Br                                                                              NMR (DMSO-d.sub.6) δ: 4.90 (2H, s), 7.10                                (1H, t, J=6.5Hz), 8.04-8.20 (1H, m), 8.45 (1H,                                d, J=1.7Hz)                                          73   H                                                                                ##STR162##     Cl                                                                              Light pink powder NMR (DMSO-d.sub.6) δ:                                 2.05 (3H, s), 2.84-3.a0 (4H, m), 3.52-3.67 (4H,                               m), 3.92 (3H, s), 5.13 (2H, s), 7.12 (1H, d,                                  J=8.6Hz), 7.45 (1H, d, J=2.0Hz), 7.73 (1H, dd,                                J=2.0Hz, 8.6Hz)                                      74   H                                                                                ##STR163##     Br                                                                              NMR (CDCl.sub.3) δ: 4.50 (2H, s),                                       9.07-9.49 (3H, m)                                    __________________________________________________________________________

Reference Examples 75-77

Compounds shown in Table 5 were obtained by using respective startingmaterials, in the same procedure as in Reference Examples 1 or 2.

                                      TABLE 5                                     __________________________________________________________________________     ##STR164##                                                                   Reference                                                                     Example                                                                             R.sup.1        Properties                                               __________________________________________________________________________    75                                                                                   ##STR165##    NMR (CDCl.sub.3)δ: 4.00 (3H, s), 7.25 (1H, d,                           J=8.8Hz), 7.15 (1H, brs), 7.52 (1H, brs), 8.08 (1H,                           dd, J=2.5Hz, 8.8Hz), 8.46 (1H, d, J=2.5Hz), 11.17                             (1H, s)                                                  76                                                                                   ##STR166##    NMR (CDCl.sub.3) δ: 1.05 (3H, t, J=7.5Hz),                              1.46 (3H, t, J=7.0Hz), 1.79-1.93 (2H, m), 4.02 (2H,                           t, J=6.8Hz), 4.13 (2H, q, J=7.0Hz), 6.85 (1H, d,                              J=8.4Hz), 7.16 (1H, brs), 7.37 (1H, dd, J=2.3Hz,                              8.4Hz), 7.54 (1H, brs), 7.60 (1H, d, J=2.3Hz)            77                                                                                   ##STR167##    NMR (CDCl.sub.3) δ: 1.43 (3H, t, J=7.0Hz),                              1.50 (3H, t, J=7.0Hz), 4.01-4.23 (4H, m), 6.43 (1H,                           d, J=2.3Hz), 6.53 (1H, dd, J=9.0Hz, 2.3Hz), 7.98                              (1H, brs), 8.69 (1H, d, J=9.0Hz), 9.23 (1H,              __________________________________________________________________________                         brs)                                                 

Reference Examples 78-97

Compounds shown in Table 6 were obtained by using respective startingmaterials, in the same procedure as in Reference Example 3 or 4.

                                      TABLE 6                                     __________________________________________________________________________     ##STR168##                                                                                          Crystal form                                                                             Melting point                               Reference              (recrystallization                                                                       (°C.)                                Example                                                                            R.sup.2                                                                          R.sup.3      Y solvent)   (salt form)                                 __________________________________________________________________________    78   H                                                                                 ##STR169##  Br           NMR.sup.1)  (-)                             79   "                                                                                 ##STR170##  "            NMR.sup.2)  (1)                             80   "                                                                                 ##STR171##  "            NMR.sup.3)  (1)                             81   H                                                                                 ##STR172##  "            NMR.sup.4)  (-)                             82   "                                                                                 ##STR173##  "            NMR.sup.5)  (-)                             83   "                                                                                 ##STR174##  "            NMR.sup.6)  (-)                             84   H                                                                                 ##STR175##  "            NMR.sup.7)  (-)                             85   "                                                                                 ##STR176##  "            NMR.sup.8)  (-)                             86   "                                                                                 ##STR177##  "            NMR.sup.9)  (-)                             87   H                                                                                 ##STR178##  Br           NMR.sup.10)  (-)                            88   "                                                                                 ##STR179##  Cl                                                                              White powdery crystals (ethyl acetate-n- hexane)                                         105-107 (-)                                 89   "                                                                                 ##STR180##  " White powdery crystals (ethyl acetate-n- hexane)                                         99-100 (-)                                  90   "                                                                                 ##STR181##  " White powdery crystals (ethyl acetate)                                                   109-110 (-)                                 91   H                                                                                 ##STR182##  Cl                                                                              Colorless prismatic crystals (ethyl acetate-n-                                hexane)    126-127 (-)                                 92   "                                                                                 ##STR183##  Br                                                                              Light brown acicular crystals (dichloro-methane-                              ethanol)   130-131 (-)                                 93   "                                                                                 ##STR184##  Cl           NMR.sup.11)  (-)                            94   CH.sub.3                                                                          ##STR185##  Br                                                                              White acicular crystals (n-hexane-dichloro-                                   methane)   102-103 (-)                                 95   H                                                                                 ##STR186##  Cl                                                                              White acicular crystals (ethyl acetate-n- hexane)                                        121-122 (-)                                 96   "                                                                                 ##STR187##  "            NMR.sup.12)  (-)                            97   "                                                                                 ##STR188##  Br           NMR.sup.13)  (-)                            __________________________________________________________________________

NMR¹) Compound of Reference Example 78

NMR (CDCl₃) δppm:

2.65 (3H, s)

4.65 (2H, s)

7.98-8.16 (5H, m)

NMR²) Compound of Reference Example 79

NMR (CDCl₃) δppm:

4.06 (3H, s)

4.57 (2H, s)

8.91 (1H, t, J=1.9Hz)

8.98 (1H, t, J=1.9Hz)

9.05 (1H, t, J=1.9Hz)

NMR³) Compound of Reference Example 80

NMR (CDCl₃) δppm:

4.00 (3H, s)

4.42 (2H, s)

7.76 (1H, t, J=8.0Hz)

8.11 (1H, dd, J=1.1Hz, J=8.0Hz)

8.32 (1H, dd, J=1.1Hz, J=8.0Hz)

NMR⁴) Compound of Reference Example 81

NMR (CDCl₃) δppm:

3.88 (3H, s)

4.52 (2H, s)

5.62 (2H, brs)

8.40 (1H, d, J=1.8Hz)

8.42 (1H, d, J=1.8Hz)

NMR⁵) Compound of Reference Example 82

NMR (CDCl₃) δppm:

4.45 (2H, s)

7.65 (1H, m)

7.67 (1H, m)

8.21 (1H, m)

8.28 (1H, m)

NMR⁶) Compound of Reference Example 83

NMR (CDCl₃) δppm:

2.27 (3H, s)

2.62 (3H, s)

3.94 (3H, s)

4.43 (2H, s)

8.30 (1H, s)

8.48 (1H, s)

NMR⁷) Compound of Reference Example 84

NMR (CDCl₃) δppm:

2.34 (3H, s)

3.94 (3H, s)

4.52 (2H, s)

7.89 (1H, m)

7.97 (1H, m)

8.43 (1H, m)

NMR⁸) Compound of Reference Example 85

NMR (CDCl₃) δppm:

2.39 (3H, s)

3.96 (3H, s)

4.46 (2H, s)

7.21 (1H, d, J=8.6Hz)

8.29 (1H, dd, J=2.0Hz, J=8.6Hz)

8.58 (1H, d, J=2.0Hz)

NMR⁹) Compound of Reference Example 86

NMR (CDCl₃) δppm:

3.94 (3H, s)

4.54 (2H, s)

7.09 (1H, d, J=8.7Hz)

8.15 (1H, dd, J=2.0Hz, J=8.7Hz)

8.49 (1H, d, J=2.0Hz)

12.11 (1H, s)

NMR¹⁰) Compound of Reference Example 87

NMR (CDCl₃) δppm:

4.00 (3H, s)

4.64 (2H, s)

8.76 (2H, d, J=2.2Hz)

8.85 (1H, d, J=2.2Hz)

12.50 (1H, brs)

NMR¹¹) Compound of Reference Example 93

NMR (CDCl₃) δppm:

1.27 (3H, t, J=7.5Hz)

2.68 (2H, t, J=7.5Hz)

4.67 (3H, s)

5.73 (1H, s)

6.85 (1H, d, J=8.4Hz)

7.75 (1H, dd, J=2.3Hz, 8.4Hz)

7.82 (1H, d, J=2.3Hz)

NMR¹²) Compound of Reference Example 96

NMR (CDCl₃) δppm:

3.91 (3H, s)

4.48 (2H, s)

7.35 (1H, m)

7.71 (1H, m)

10.48 (1H, brs)

NMR¹³) Compound of Reference Example 97

NMR (DMSO-d₆) δppm:

5.04 (2H, s)

7.56 (1H, brs)

8.10-8.39 (3H, m)

Reference Examples 98-116

Compounds shown in Table 7 were obtained using respective startingmaterials, in the same procedure as in Reference Example 3 or 4.

                                      TABLE 7                                     __________________________________________________________________________     ##STR189##                                                                                             Crystal form                                        Reference                 (recrystallization                                                                    Melting point                               Example                                                                            R.sup.2                                                                         R.sup.3          Y solvent)                                                                              (°C.) (salt form)                    __________________________________________________________________________     98  H                                                                                ##STR190##      Cl        NMR.sup.14)  (-)                             99  "                                                                                ##STR191##      "         NMR.sup.15)  (-)                            100  H                                                                                ##STR192##      Cl                                                                              Brown solid                                                                           NMR.sup.16)  (-)                            101  "                                                                                ##STR193##      "         NMR.sup.17)  (-)                            102  "                                                                                ##STR194##      " White acicular crystals                                                               NMR.sup.18)  (-)                            103  H                                                                                ##STR195##      Cl                                                                              White acicular crystals (ethanol)                                                     107-108 (-)                                 104  "                                                                                ##STR196##      Br        NMR.sup.19)  (-)                            105  "                                                                                ##STR197##      "         NMR.sup.20)  (-)                            106  "                                                                                ##STR198##      "         NMR.sup.21)  (-)                            107  H                                                                                ##STR199##      Br        NMR.sup.22)  (-)                            108  "                                                                                ##STR200##      "         NMR.sup.23)  (HBr)                          109  "                                                                                ##STR201##      "         NMR.sup.24)  (HBr)                          110  "                                                                                ##STR202##      "         NMR.sup.25)  (HBr)                          111  H                                                                                ##STR203##      Br        NMR.sup.26)  (-)                            112  "                                                                                ##STR204##      "         NMR.sup.27)  (HBr)                          113  "                                                                                ##STR205##      "         NMR.sup.28)  (-)                            114  "                                                                                ##STR206##      "         NMR.sup.29)  (HBr)                          115  H                                                                                ##STR207##      Br        NMR.sup.30)  (HBr)                          __________________________________________________________________________

NMR data of the compounds of Reference Examples 98-102, 105-113 and115-116

NMR¹⁴) : Compound of Reference Example 98

¹ H-NMR(CDCl₃) δ: 2.59 (3H, s), 4.00 (3H, s), 4.64 (2H, s), 6.90 (1H,s), 8.25 (1H, s), 11.12 (1H, s)

NMR¹⁵) : Compound of Reference Example 99

¹ H-NMR(CDCl₃) δ: 2.33 (3H, s), 3.96 (3H, s), 4.62 (2H, s), 6.79 (1H, d,J=8.1Hz), 7.80 (1H, d, J=8.1Hz), 11.40 (1H, s)

NMR¹⁶) : Compound of Reference Example 100

¹ H-NMR(CDCl₃) δ: 1.25 (3H, t, J=7.5Hz), 2.73 (2H, q, J=7.5Hz), 4.00(3H, s), 4.67 (2H, s), 7.98 (1H, d, J=1.7Hz), 8.35 (1H, d, J=1.7Hz),11.66 (1H, s)

NMR¹⁷) : Compound of Reference Example 101

¹ H-NMR(CDCl₃) δ: 4.06 (3H, s), 4.68 (2H, s), 4.75 (2H, s), 7.74 (1H,dd, J=2.0Hz, 6.7Hz), 8.06 (1H, dd, J=2.0Hz, 6.7Hz), 8.19 (1H, d,J=2.3Hz), 8.55 (1H, d, J=2.3Hz), 12.04 (1H, s)

NMR¹⁸) : Compound of Reference Example 102

¹ H-NMR(CDCl₃) δ: 3.99 (3H, s), 4.75 (2H, s) 7.00 (1H, t, J=7.8Hz), 7.56(1H, d, J=7.8Hz), 7.99 (1H, dd, J=1.8Hz, 7.8Hz), 8.03 (2H, d, J=8.5Hz),11.43 (1H, s), 7,74 (2H, d, J=8.5Hz)

NMR¹⁹) : Compound of Reference Example 104

¹ H-NMR(CDCl₃) δ: 3.92 (3H, s), 4.28 (2H, s), 6.90 (1H, dd, J=2.1Hz,3.3Hz), 6.95 (1H, dd, J=2.1Hz, 3.3Hz), 9.90 (1H, brs)

NMR²⁰) : Compound of Reference Example 105

¹ H-NMR(CDCl₃) δ: 3.95 (3H, s), 4.42 (2H, s), 7.26 (1H, d, J=3.7Hz),7.34 (1H, d, J=3.7Hz)

NMR²¹) : Compound of Reference Example 106

¹ H-NMR(CDCl₃) δ: 1.47 (3H, t, J=7.1Hz), 2.61 (3H, s), 4.46 (2H, q,J=7.1Hz), 5.00 (2H, s), 8.21 (2H, m)

NMR²²) : Compound of Reference Example 107

¹ H-NMR(CDCl₃) δ: 1.40 (3H, t, J=7.1Hz), 4.36 (2H, s), 4.38 (2H, q,J=7.1Hz), 7.74 (1H, d, J=4.0Hz), 7.78 (1H, d, J=4.0Hz)

NMR²³) : Compound of Reference Example 108

¹ H-NMR(CDCl₃) δ: 4.10 (3H, s), 4.92 (2H, s), 9.41-10.01 (3H, m)

NMR²⁴) : Compound of Reference Example 109

¹ H-NMR(DMSO-d₆) δ: 5.05 (2H, s), 8.20 (1H, dd, J=1.6Hz, 5.0Hz), 8.42(1H, dd, J=0.9Hz, 1.6Hz), 9.01 (1H, dd, J=0.9Hz, 5.0Hz)

NMR²⁵) : Compound of Reference Example 110

¹ H-NMR(DMSO-d₆) δ: 2.73 (3H, s), 5.03 (2H, s), 8.17 (1H, brs), 8.26(1H, brs), 8.44 (1H, d, J=2.1Hz), 8.54 (1H, d, J=2.1Hz)

NMR²⁶) : Compound of Reference Example 111

¹ H-NMR(CDCl₃) δ: 4.01 (3H, s), 4.88 (2H, s), 8.15 (1H, dd, J=0.7Hz,8.1Hz), 8.45 (1H, dd, J=2.1Hz, 8.1Hz), 9.13 (1H, m)

NMR²⁷) : Compound of Reference Example 112

¹ H-NMR(CDCl₃) δ: 1.45 (3H, t, J=7.1Hz), 4.52 (2H, q, J=7.1Hz), 4.78(2H, s), 8.49 (1H, d, J=8.1Hz). 8.96 (1H, dd, J=1.9Hz, 8.1Hz), 9.55 (1H,d, J=1.9Hz)

NMR²⁸) : Compound of Reference Example 113

¹ H-NMR(DMSO-d₆) δ: 2.77 (3H, s), 5.08 (2H, s), 8.11 (1H, d, J=5.7Hz),8.25 (1H, s), 8.96 (1H, d, J=5.7Hz)

NMR²⁹) : Compound of Reference Example 114

¹ H-NMR(CDCl₃) δ: 4.11 (3H, s), 4.76 (2H, s), 7.60 (1H, dd, J=4.8Hz,7.9Hz), 8.12 (1H, dd, J=1.5Hz, 7.9Hz), 8.96 (1H, dd, J=1.5Hz, 4.8Hz)

NMR³⁰) : compound of Reference Example 115

¹ H-NMR(DMSO-d₆) δ: 2.82 (3H, s), 2.87 (3H, s), 5.20 (2H, s), 8.09 (1H,brs), 8.42 (1H, brs), 9.01 (1H, s)

Example 1

In 20 ml of ethanol were suspended 367 mg of3',4'-dihydroxy-2-chloroacetophenone and 430 mg of3,4-dimethoxythiobenzamide. The suspension was refluxed for 3 hours withheating. After cooling, the resulting crystals were collected byfiltration, ethanol-washed and dried. The dried material wasrecrystallized from ethanol to obtain 160 mg of2-(3,4-dimethoxyphenyl)-4-(3,4-dihydroxyphenyl)thiazole hydrochloride asyellow acicular crystals.

M.p.: 146°-148° C.

Examples 2-136

Compounds shown in Tables 8 and 9 were obtained by using respectivestarting materials, in the same procedure as in Example 1.

                                      TABLE 8                                     __________________________________________________________________________     ##STR208##                                                                   __________________________________________________________________________    Compound of Example 2                                                          ##STR209##            R.sup.2 = H,                                                                   ##STR210##                                            Crystal form: yellow prismatic (recrystallized                                from methanol)                                                                Mp: 182-183° C. (decomposed, 1/4 FeCl.sub.2 salt)                      Compound of Example 3                                                          ##STR211##            R.sup.2 = H,                                                                   ##STR212##                                            Crystal form: light brown powdery (recrystallized                             from dimethylformamide)                                                       Mp: 300° C. or above                                                   Compound of Example 4                                                          ##STR213##            R.sup.2 = H,                                                                   ##STR214##                                            Crystal form: colorless acicular (recrystallized                              from diethyl ether-n-hexane)                                                  Mp: 59-60° C.                                                          Compound of Example 5                                                          ##STR215##            R.sup.2 = H,                                                                   ##STR216##                                            Crystal form: light yellow prismatic (recrystal-                              lized from ethanol)                                                           Mp: 172-173° C.                                                        Compound of Example 6                                                          ##STR217##            R.sup.2 = H,                                                                   ##STR218##                                            Crystal form: light brown acicular (recrystallized                            from ethanol)                                                                 Mp: 88-89° C. (HCl salt)                                               Compound of Example 7                                                          ##STR219##            R.sup.2 = H,                                                                   ##STR220##                                            Crystal form: brown powdery (recrystallized from                              ethanol acetate)                                                              Mp: 140-141° C.                                                        Compound of Example 8                                                          ##STR221##            R.sup.2 = H,                                                                   ##STR222##                                            Crystal form: light brown plate (recrystallized                               from ethanol)                                                                 Mp: 129-130° C.                                                        Compound of Example 9                                                          ##STR223##            R.sup.2 = H,                                                                   ##STR224##                                            Crystal form: colorless acicular (recrystallized                              from methanol-ethyl acetate)                                                  Mp: 188-189° C.                                                        Compound of Example 10                                                         ##STR225##            R.sup.2 = H,                                                                   ##STR226##                                            Crystal form: light brown acicular (recrystallized                            from ethyl acetate)                                                           Mp: 129-130° C.                                                        Compound of Example 11                                                         ##STR227##                                                                   R.sup.2 = H,                                                                                          ##STR228##                                            Crystal form: light green columnar (recrystallized                            from methanol)                                                                Mp: 135-136° C.                                                        Compound of Example 12                                                         ##STR229##            R.sup.2 = H,                                                                   ##STR230##                                            Crystal form: colorless acicular (recrystallized                              from diethyl ether-n-hexane)                                                  Mp: 57.5-58.5° C.                                                      Compound of Example 13                                                         ##STR231##            R.sup.2 = H,                                                                   ##STR232##                                            Crystal form: white acicular (recrystallized from                             diethyl ether-n-hexane)                                                       Mp: 91.5-92° C.                                                        Compound of Example 14                                                         ##STR233##            R.sup.2 = H,                                                                   ##STR234##                                            Crystal form: light brown plate (recrystallized                               from methanol)                                                                Mp: 206-207° C. (decomposed)                                           Compound of Example 15                                                         ##STR235##            R.sup.2 = H,                                                                   ##STR236##                                            Crystal form: orange powdery (recrystallized from                             ethanol-water)                                                                Mp: 209-210° C. (decomposed, HCl salt)                                 Compound of Example 16                                                         ##STR237##            R.sup.2 = H,                                                                   ##STR238##                                            Crystal form: colorless acicular (recrystallized                              from diethyl ether-n-hexane)                                                  Mp: 83-84° C.                                                          Compound of Example 17                                                         ##STR239##            R.sup.2 = H,                                                                   ##STR240##                                            Crystal form: colorless acicular (recrystallized                              from diethyl ether-n-hexane)                                                  Mp: 76-78° C.                                                          Compound of Example 18                                                         ##STR241##            R.sup.2 = H,                                                                   ##STR242##                                            Crystal form: brown powdery (recrystallized from                              dimethylformamide-water)                                                      Mp: 300° C. or above                                                   Compound of Example 19                                                         ##STR243##            R.sup.2 = H,                                                                   ##STR244##                                            Crystal form: yellow powdery (recrystallized from                             dioxane-water)                                                                Mp: 280-281° C.                                                        Compound of Example 20                                                         ##STR245##            R.sup.2 = H,                                                                   ##STR246##                                            Crystal form: yellow powdery (recrystallized from                             dimethylformamide-water)                                                      Mp: 262-263° C.                                                        Compound of Example 21                                                         ##STR247##            R.sup.2 = H,                                                                   ##STR248##                                            Crystal form: light yellow powdery (recrystallized                            from ethyl acetate)                                                           Mp: 180-181° C. (decomposed)                                           Compound of Example 22                                                         ##STR249##            R.sup.2 = H,                                                                   ##STR250##                                            Crystal form: yellow prismatic (recrystallized from                           ethanol)                                                                      Mp: 124-126° C. (HCl salt)                                             Compound of Example 23                                                         ##STR251##            R.sup.2 = H,                                                                   ##STR252##                                            Crystal form: yellow acicular (recrystallized from                            ethyl acetate-diethyl ether)                                                  Mp: 128-129° C. (HCl-1/2H.sub.2 O salt)                                Compound of Example 24                                                         ##STR253##            R.sup.2 = H,                                                                   ##STR254##                                            Crystal form: light brown powdery (recrystallized                             from dimethylformamide-water)                                                 Mp: 187-188° C.                                                        Compound of Example 25                                                         ##STR255##            R.sup.2 = H,                                                                   ##STR256##                                            Crystal form: yellow powdery (recrystallized from                             ethanol)                                                                      Mp: 248-249° C. (HCl salt)                                             Compound of Example 26                                                         ##STR257##            R.sup.2 = H,                                                                   ##STR258##                                            Crystal form: white acicular (recrystallized from                             ethanol)                                                                      Mp: 205-206° C.                                                        Compound of Example 27                                                         ##STR259##            R.sup.2 = H,                                                                   ##STR260##                                            Crystal form: light brown powdery (recrystallized                             from ethanol)                                                                 Mp: 156-158° C. (HCl salt)                                             Compound of Example 28                                                         ##STR261##            R.sup.2 = H,                                                                   ##STR262##                                            Crystal form: light brown acicular (recrystallized                            from dimethylformamide)                                                       Mp: 282-284° C. (decomposed)                                           Compound of Example 29                                                         ##STR263##            R.sup.2 = H,                                                                   ##STR264##                                            Crystal form: colorless acicular (recrystallized                              from dimethylformamide)                                                       Mp: 199-200° C.                                                        Compound of Example 30                                                         ##STR265##            R.sup.2 = H,                                                                   ##STR266##                                            Crystal form: colorless prismatic (recrystallized                             from ethyl acetate)                                                           Mp: 163-163.5° C.                                                      Compound of Example 31                                                         ##STR267##            R.sup.2 = H,                                                                   ##STR268##                                            Crystal form: light yellow plate (recrystallized                              from n-hexane)                                                                Mp: 98-99° C.                                                          Compound of Example 32                                                         ##STR269##            R.sup.2 = H,                                                                   ##STR270##                                            Crystal form: light yellow powdery (recrystallized                            from dimethylformamide)                                                       Mp: 249-250° C.                                                        Compound of Example 33                                                         ##STR271##            R.sup.2 = H,                                                                   ##STR272##                                            Crystal form: white acicular (recrystallized from                             ethanol)                                                                      Mp: 149-150° C.                                                        Compound of Example 34                                                         ##STR273##            R.sup.2 = H,                                                                   ##STR274##                                            Crystal form: white acicular (recrystallized from                             methanol)                                                                     Mp: 160-161° C.                                                        Compound of Example 35                                                         ##STR275##            R.sup.2 = H,                                                                   ##STR276##                                            Crystal form: light yellow powdery (recrystallized                            from dimethylformamide-water)                                                 Mp: 143.5-144° C.                                                      Compound of Example 36                                                         ##STR277##            R.sup.2 = H,                                                                   ##STR278##                                            Crystal form: white powdery (recrystallized from                              ethanol)                                                                      Mp: 94-95° C.                                                          Compound of Example 37                                                         ##STR279##            R.sup.2 = H,                                                                   ##STR280##                                            Crystal form: light brown acicular (recrystallized                            from ethanol)                                                                 Mp: 151-152° C.                                                        Compound of Example 38                                                         ##STR281##            R.sup.2 = H,                                                                   ##STR282##                                            Crystal form: white acicular (recrystallized from                             petroleum ether)                                                              Mp: 67-68° C.                                                          Compound of Example 39                                                         ##STR283##            R.sup.2 = H,                                                                   ##STR284##                                            Crystal form: white acicular (recrystallized from                             methanol)                                                                     Mp: 122-123° C.                                                        Compound of Example 40                                                         ##STR285##            R.sup.2 = H,                                                                   ##STR286##                                            Crystal form: light yellow powdery (recrystallized                            from ethanol)                                                                 Mp: 152.5-153.5° C.                                                    Compound of Example 41                                                         ##STR287##            R.sup.2 = H,                                                                   ##STR288##                                            Crystal form: light yellow prismatic (recrystallized                          from ethanol-water)                                                           Mp: 83-84° C.                                                          Compound of Example 42                                                         ##STR289##            R.sup.2 = H,                                                                   ##STR290##                                            Crystal form: yellow powdery (recrystallized from                             ethanol)                                                                      Mp: 69-70° C.                                                          Compound of Example 43                                                         ##STR291##            R.sup.2 = H,                                                                   ##STR292##                                            Crystal form: colorless acicular (recrystallized                              from ethyl acetate)                                                           Mp: 174.5-175.5° C.                                                    Compound of Example 44                                                         ##STR293##            R.sup.2 = H,                                                                   ##STR294##                                            Crystal form: colorless acicular (recrystallized                              from ethanol)                                                                 Mp: 147.5-148.5° C.                                                    Compound of Example 45                                                         ##STR295##            R.sup.2 = H,                                                                   ##STR296##                                            Crystal form: light yellow acicular (recrystallized                           from methanol)                                                                Mp: 151-152° C.                                                        Compound of Example 46                                                         ##STR297##            R.sup.2 = H,                                                                   ##STR298##                                            Crystal form: colorless plate (recrystallized from                            diethyl ether-petroleum ether)                                                Mp: 150-152° C.                                                        Compound of Example 47                                                         ##STR299##            R.sup.2 = H,                                                                   ##STR300##                                            Crystal form: white powdery (recrystallized from                              ethyl acetate-n-hexane)                                                       Mp: 126-127° C.                                                        Compound of Example 48                                                         ##STR301##            R.sup.2 = H,                                                                   ##STR302##                                            Crystal form: yellow powdery (recrystallized from                             ethanol-diethyl ether)                                                        Mp: 124-126° C. (HCl salt)                                             Compound of Example 49                                                         ##STR303##            R.sup.2 = H,                                                                   ##STR304##                                            Crystal form: white powdery (recrystallized from                              dimethylformamide)                                                            Mp: 263-265° C.                                                        Compound of Example 50                                                         ##STR305##            R.sup.2 = H,                                                                   ##STR306##                                            Crystal form: colorless prismatic (recrystallized                             from dimethylformamide-water)                                                 Mp: 249-250° C. (decomposed)                                           Compound of Example 51                                                         ##STR307##            R.sup.2 = H,                                                                   ##STR308##                                            Crystal form: light brown prismatic (recrystallized                           from dimethylformamide)                                                       Mp: 225-226° C.                                                        Compound of Example 52                                                         ##STR309##            R.sup.2 = H,                                                                   ##STR310##                                            Crystal form: light brown acicular (recrystallized                            from dimethylformamide)                                                       Mp: 250-251° C.                                                        Compound of Example 53                                                         ##STR311##            R.sup.2 = H,                                                                   ##STR312##                                            Crystal form: white powdery (recrystallized from                              dimethylformamide)                                                            Mp: 145-146° C.                                                        Compound of Example 54                                                         ##STR313##            R.sup.2 = H,                                                                   ##STR314##                                            Crystal form: light brown acicular (recrystallized                            from dimethylformamide-methanol)                                              Mp: 182-183° C.                                                        Compound of Example 55                                                         ##STR315##            R.sup.2 = H,                                                                   ##STR316##                                            Crystal form: light brown prismatic (recrystallized                           from dimethylformamide-methanol)                                              Mp: 184-185° C.                                                        Compound of Example 56                                                         ##STR317##            R.sup.2 = H,                                                                   ##STR318##                                            Crystal form: white prismatic (recrystallized from                            dioxane)                                                                      Mp: 223-234° C.                                                        Compound of Example 57                                                         ##STR319##            R.sup.2 = H,                                                                   ##STR320##                                            Crystal form: light brown granular (recrystallized                            ethanol)                                                                      Mp: 178-179°                                                           Compound of Example 58                                                         ##STR321##            R.sup.2 = H,                                                                   ##STR322##                                            Crystal form: light brown powdery (recrystallized                             from ethanol-water)                                                           Mp: 159-161° C. (HCl salt)                                             Compound of Example 59                                                         ##STR323##            R.sup.2 = H,                                                                   ##STR324##                                            Crystal form: white powdery (recrystallized from                              dimethylformamide)                                                            Mp: 300° or above                                                      Compound of Example 60                                                         ##STR325##            R.sup.2 = H,                                                                   ##STR326##                                            Crystal form: light brown powdery (recrystallized                             from dimethylformamide)                                                       Mp: 215-216° C.                                                        Compound of Example 61                                                         ##STR327##            R.sup.2 = H,                                                                   ##STR328##                                            Crystal form: colorless acicular (recrystallized                              from acetonitrile)                                                            Mp: 156-157° C.                                                        Compound of Example 62                                                         ##STR329##            R.sup.2 = H,                                                                   ##STR330##                                            Crystal form: light yellow powdery (recrystallized                            from ethanol)                                                                 Mp: 128-130° C. (HCl salt)                                             Compound of Example 63                                                         ##STR331##            R.sup.2 = H,                                                                   ##STR332##                                            Crystal form: colorless acicular (recrystallized                              from ethyl acetate)                                                           Mp: 155-156° C.                                                        Compound of Example 64                                                         ##STR333##            R.sup.2 = H,                                                                   ##STR334##                                            Crystal form: light yellow acicular (recrystallized                           from dimethylformamide-water)                                                 Mp: 206-208° C.                                                        Compound of Example 65                                                         ##STR335##            R.sup.2 = H,                                                                   ##STR336##                                            Crystal form: light brown acicular (recrystallized                            from dimethylformamide)                                                       Mp: 168-169° C.                                                        Compound of Example 66                                                         ##STR337##            R.sup.2 = H,                                                                   ##STR338##                                            Crystal form: white powdery (recrystallized from                              ethanol):                                                                     Mp: 191-192° C.                                                        Compound of Example 67                                                         ##STR339##            R.sup.2 = H,                                                                   ##STR340##                                            Crystal form: white powdery (recrystallized                                   from dimethylformamide-methanol)                                              Mp: 226-227° C.                                                        Compound of Example 68                                                         ##STR341##            R.sup.2 = H,                                                                   ##STR342##                                            Crystal form: light brown acicular (recrystallized                            from dimethylformamide-water)                                                 Mp: 227-228° C.                                                        Compound of Example 69                                                         ##STR343##            R.sup.2 = H,                                                                   ##STR344##                                            Crystal form: white powdery (recrystallized from                              methanol)                                                                     Mp: 271-272° C.                                                        Compound of Example 70                                                         ##STR345##            R.sup.2 = H,                                                                   ##STR346##                                            Crystal form: yellow powdery (recrystallized from                             methanol)                                                                     Mp: 165-167° C. (decomposed, 2 HCl salt)                               Compound of Example 71                                                         ##STR347##            R.sup.2 = H,                                                                   ##STR348##                                            Crystal form: white powdery (recrystallized from                              diethyl ether-pertroleum ether)                                               Mp: 114-115° C.                                                        Compound of Example 72                                                         ##STR349##            R.sup.2 = H,                                                                   ##STR350##                                            Crystal form: white powdery (recrystallized from                              ethanol-n-hexane)                                                             Mp: 229-230° C.                                                        Compound of Example 73                                                         ##STR351##            R.sup.2 = H,                                                                   ##STR352##                                            Crystal form: Orange plate (recrystallized from                               ethanol)                                                                      Mp: 192-192.5° C.                                                      Compound of Example 74                                                         ##STR353##            R.sup.2 = H,                                                                   ##STR354##                                            Crystal form: light yellow prismatic (recrystallized                          from ethanol-n-hexane)                                                        Mp: 196-197° C.                                                        Compound of Example 75                                                         ##STR355##            R.sup.2 = H,                                                                   ##STR356##                                            Crystal form: light brown powdery (recrystallized                             from dimethylformamide)                                                       Mp: 203-204° C.                                                        Compound of Example 76                                                         ##STR357##            R.sup.2 = H,                                                                   ##STR358##                                            Crystal form: white powdery (recrystallized from                              diethyl ether)                                                                Mp: 111-112° C.                                                        Compound of Example 77                                                         ##STR359##            R.sup.2 = H,                                                                   ##STR360##                                            Crystal form: yellow acicular (recrystallized                                 from acetonitrile)                                                            Mp: 219-220.5° C.                                                      Compound of Example 78                                                         ##STR361##            R.sup.2 = H,                                                                   ##STR362##                                            Crystal form: light brown powdery (recrystallized                             from acetonitrile)                                                            Mp: 172.5-173.5° C.                                                    Compound of Example 79                                                         ##STR363##            R.sup.2 = H,                                                                   ##STR364##                                            Crystal form: light yellow powdery (recrystallized                            from ethanol-n-hexane)                                                        Mp: 203-204° C.                                                        Compound of Example 80                                                         ##STR365##            R.sup.2 = H,                                                                   ##STR366##                                            Crystal form: yellow acicular (recrystallized from                            ethanol)                                                                      Mp: 177-178° C.                                                        Compound of Example 81                                                         ##STR367##            R.sup.2 = H,                                                                   ##STR368##                                            Crystal form: light yellow powdery (recrystallized                            from acetonitrile)                                                            Mp: 224-225° C.                                                        Compound of Example 82                                                         ##STR369##            R.sup.2 = H,                                                                   ##STR370##                                            Crystal form: white acicular (recrystallized                                  from ethanol-water)                                                           Mp: 125-126° C.                                                        Compound of Example 83                                                         ##STR371##            R.sup.2 = H,                                                                   ##STR372##                                            Crystal form: yellow prismatic (recrystallized from                           ethyl acetate-n-hexane)                                                       Mp: 147-148° C.                                                        Compound of Example 84                                                         ##STR373##                                                                                           ##STR374##                                                                    ##STR375##                                            Crystal form: light yellow powdery (recrystallized                            from isopropanol)                                                             Mp: 202-204° C. (HBr salt)                                             Compound of Example 85                                                         ##STR376##            R.sup.2 = H,                                                                   ##STR377##                                            Crystal form: brown plate (recrystallized from                                ethyl acetate)                                                                Mp: 131-132° C.                                                        Compound of Example 86                                                         ##STR378##            R.sup.2 = Br,                                                                  ##STR379##                                            Crystal form: colorless acicular (recrystallized                              from ethanol)                                                                 Mp: 147-149°                                                           Compound of Example 87                                                         ##STR380##            R.sup.2 = CO.sub.2 C.sub.2 H.sub.5,                                           R.sup.3 = CH.sub.3                                     Crystal form: white powdery (recrystallized from                              ethanol-water)                                                                Mp: 147-148° C. (HCl salt)                                             Compound of Example 88                                                         ##STR381##            R.sup.2 = H,                                           R.sup.3 = CH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                   Crystal form: white prismatic (recrystallized from                            ethanol)                                                                      Mp: 119-120° C. (HCl salt)                                             Compound of Example 89                                                         ##STR382##            R.sup.2 = H,                                           R.sup.3 = CH.sub.2 CONH.sub.2                                                 Crystal form: white prismatic (recrystallized from                            ethanol)                                                                      Mp: 198-200° C. (decomposed, HCl salt)                                 Compound of Example 90                                                         ##STR383##            R.sup.2 = H,                                                                   ##STR384##                                            Crystal form: white powdery (recrystallized from                              ethanol-water)                                                                Mp: 118-119° C.                                                        Compound of Example 91                                                         ##STR385##            R.sup.2 = H,                                                                   ##STR386##                                            Crystal form: yellow columnar (recrystallized from                            ethanol)                                                                      Mp: 176-177° C.                                                        Compound of Example 92                                                         ##STR387##            R.sup.2 = H,                                                                   ##STR388##                                            Crystal form: light brown acicular (recrystallized                            from ethanol)                                                                 Mp: 184-185° C.                                                        Compound of Example 93                                                         ##STR389##            R.sup.2 = H,                                                                   ##STR390##                                            Crystal form: yellow powdery (recrystallized from                             ethanol)                                                                      Mp: 255-258° C. (decomposed, HBr salt)                                 Compound of Example 94                                                         ##STR391##            R.sup.2 = H,                                                                   ##STR392##                                            Crystal form: light brown acicular (recrystallized                            from DMF)                                                                     Mp: 235-236° C.                                                        Compound of Example 95                                                         ##STR393##            R.sup.2 = H,                                                                   ##STR394##                                            Crystal form: light brown powdery (recrystallized                             from dimethylformamide)                                                       Mp: 236-237° C.                                                        Compound of Example 96                                                         ##STR395##                                                                                           ##STR396##                                                                   R.sup.3 = H                                            Crystal form: white powdery (recrystallized from                              methanol)                                                                     Mp: 235-236° C.                                                        Compound of Example 97                                                         ##STR397##            R.sup.2 = H,                                                                   ##STR398##                                            Crystal form: colorless prismatic (recrystallized                             from ethyl acetate)                                                           Mp: 198-199° C.                                                        Compound of Example 98                                                         ##STR399##                                                                                           ##STR400##                                            Crystal form: light brown prismatic (recrystallized                           from ethanol-diethyl ether)                                                   Mp: 148-149° C. (HCl salt)                                             Compound of Example 99                                                         ##STR401##                                                                                           ##STR402##                                            Crystal form: yellow acicular (recrystallized                                 from ethanol)                                                                 Mp: 226-228° C. (HBr salt)                                             Compound of Example 100                                                        ##STR403##                                                                    ##STR404##                                                                   Crystal form: dark green acicular (recrystallized                             from ethanol)                                                                 Mp: 154-155° C. (HBr salt)                                             Compound of Example 101                                                        ##STR405##            R.sup.2 = H,                                            ##STR406##                                                                   Crystal form: light brown acicular (recrystallized                            from ethanol)                                                                 Mp: 128-129° C.                                                        Compound of Example 102                                                        ##STR407##            R.sup.2 = H,                                                                   ##STR408##                                            Crystal form: white acicular (recrystallized                                  from ethanol)                                                                 Mp: 170-171° C.                                                        Compound of Example 103                                                        ##STR409##            R.sup.2 = H,                                                                   ##STR410##                                            Crystal form: yellow acicular (recrystallized from                            chloroform-ethanol)                                                           Mp: 149-150° C.                                                        Compound of Example 104                                                        ##STR411##            R.sup.2 = H,                                                                   ##STR412##                                            Crystal form: light violet plate (recrystallized                              from ethanol)                                                                 Mp: 167-169° C. (decomposed)                                           Compound of Example 105                                                        ##STR413##            R.sup.2 = H,                                                                   ##STR414##                                            Crystal form: red powdery recrystallized from                                 ethanol)                                                                      Mp: 184-186° C. (decomposed)                                           Compound of Example 106                                                        ##STR415##            R.sup.2 = H,                                                                   ##STR416##                                            Crystal form: brown acicular (recrystallized from                             ethanol)                                                                      Mp: 221-224° C.                                                        Compound of Example 107                                                        ##STR417##            R.sup.2 = H,                                                                   ##STR418##                                            NMR(DMSO-D.sub.6)δ:                                                     10.5(2H, brs), 8.18(1H, d, J=1.7Hz), 8.09(1H, s),                             7.96(1H, dd, J=8.5Hz, 1.7Hz), 7.71(1H, d, J=8.5Hz),                           7.5-7.65(2H, m), 7.09(1H, d, J=8.4Hz), 3.86(3H, s),                           3.83(3H, s)                                                                   Compound of Example 108                                                        ##STR419##            R.sup.2 = H,                                                                   ##STR420##                                            Crystal form: colorless prismatic (recrystallized                             from ethanol)                                                                 Mp: 216-217° C.                                                        Compound of Example 109                                                        ##STR421##            R.sup.2 = H,                                                                   ##STR422##                                            Crystal form: light yellow prismatic (recrystallized                          from dimethylformamide)                                                       Mp: 263-264° C.                                                        Compound of Example 110                                                        ##STR423##            R.sup.2 = H,                                                                   ##STR424##                                            Crystal form: orange acicular (recrystallized from                            dimethylformamide)                                                            Mp: 300° C. or above                                                   Compound of Example 111                                                        ##STR425##            R.sup.2 = H,                                                                   ##STR426##                                            Crystal form: light yellow plate (recrystallized                              from dimethylformamide)                                                       Mp: 231-232° C.                                                        Compound of Example 112                                                        ##STR427##            R.sup.2 = H,                                                                   ##STR428##                                            Crystal form: light brown powdery (recrystallized                             from dioxane)                                                                 Mp: 272.5-273.5° C.                                                    Compound of Example 113                                                        ##STR429##            R.sup.2 = H,                                                                   ##STR430##                                            Crystal form: light yellow prismatic (recrystallized                          from dioxane)                                                                 Mp: 242-243° C.                                                        Compound of Example 114                                                        ##STR431##            R.sup.2 = H,                                                                   ##STR432##                                            Crystal form: light yellow acicular (recrystallized                           from dioxane)                                                                 Mp: 236-237° C.                                                        Compound of Example 115                                                        ##STR433##            R.sup.2 = H,                                                                   ##STR434##                                            Crystal form: light brown prismatic (recrystallized                           from dimethylformamide)                                                       Mp: 255-256° C.                                                        Compound of Example 116                                                        ##STR435##            R.sup.2 = H,                                                                   ##STR436##                                            Crystal form: light yellow columnar (recrystallized                           from diethylformamide)                                                        Mp: 264-265° C.                                                        Compound of Example 117                                                        ##STR437##            R.sup.2 = H,                                                                   ##STR438##                                            Crystal form: light yellow powdery (recrystallized                            from dimethylformamide)                                                       Mp: 300° C. or above                                                   Compound of Example 118                                                        ##STR439##            R.sup.2 = H,                                                                   ##STR440##                                            Crystal form: light yellow acicular (recrystallized                           from dimethylformamide)                                                       Mp: 264-265° C.                                                        Compound of Example 119                                                        ##STR441##            R.sup.2 = H,                                                                   ##STR442##                                            Crystal form: colorless acicular (recrystallized                              from acetonitrile)                                                            Mp: 209-210° C.                                                        Compound of Example 120                                                        ##STR443##            R.sup.2 = H,                                                                   ##STR444##                                            Crystal form: light yellow powdery (recrystallized                            from dimethylformamide)                                                       Mp: 300° C. or above                                                   Compound of Example 121                                                        ##STR445##            R.sup.2 = H,                                                                   ##STR446##                                            Crystal form: white powdery (recrystallized from                              dimethylformamide-water)                                                      Mp: 284-286° C.                                                        Compound of Example 122                                                        ##STR447##            R.sup.2 = H,                                                                   ##STR448##                                            Crystal form: colorless acicular (recrystallized                              from dioxane-water)                                                           Mp: 252-253° C.                                                        Compound of Example 123                                                        ##STR449##            R.sup.2 = H,                                                                   ##STR450##                                            Crystal form: light green powdery (recrystallized                             from ethanol-water)                                                           Mp: 256-258° C. HCl salt)                                              Compound of Example 124                                                        ##STR451##            R.sup.2 = H,                                                                   ##STR452##                                            Crystal form: colorless acicular (recrystallized                              from dioxane)                                                                 Mp: 191-192° C.                                                        Compound of Example 125                                                        ##STR453##            R.sup.2 = H,                                                                   ##STR454##                                            Crystal form: colorless prismatic (recrystallized                             from dioxane-water)                                                           Mp: 178-179° C.                                                        Compound of Example 126                                                        ##STR455##            R.sup.2 = H,                                                                   ##STR456##                                            Crystal form: white powdery (recrystallized from                              dimethylformamide)                                                            Mp: 185-186° C. (HCl salt)                                             Compound of Example 127                                                        ##STR457##            R.sup.2 = H,                                                                   ##STR458##                                            Crystal form: light brown acicular (recrystallized                            from chloroform-ethanol)                                                      Mp: 249-251° C.                                                        Compound of Example 130                                                        ##STR459##            R.sup.2 = H,                                                                   ##STR460##                                            Crystal form: white powdery (recrystallized from                              dimethylformamide)                                                            Mp: 300° C. or above                                                   Compound of Example 131                                                        ##STR461##            R.sup.2 = H,                                                                   ##STR462##                                            Crystal form: white powdery (recrystallized from                              ethanol)                                                                      Mp: 127-128° C.                                                        Compound of Example 132                                                        ##STR463##            R.sup.2 = H,                                                                   ##STR464##                                            Crystal form: colorless columnar (recrystallized                              from petroleum ether-diethyl ether)                                           Mp: 141-142° C.                                                        Compound of Example 133                                                        ##STR465##            R.sup.2 = H,                                                                   ##STR466##                                            Crystal form: light yellow powdery (recrystallized                            from ethanol)                                                                 Mp: 157-167° C. (decomposed, HCl salt)                                 NMR (CDCl.sub.3)δ:                                                      3.80(3H, s), 3.87(3H s), 7.06(1H, d, J=8.5Hz),                                7.56(1H, dd, J=2.1Hz, 8.5Hz), 7.65-7.82(2H, m),                               8.31(1H, t, J=6.7Hz), 8.46(1H, d, J=7.9Hz),                                   8.65-8.82(2H, m)                                                              Compound of Example 134                                                        ##STR467##            R.sup.2 = H,                                                                   ##STR468##                                            Crystal form: light yellow powdery (recrystallized                            from methanol)                                                                Mp: 270-271° C. (decomposed, 1/3 FeCl.sub.2 salt)                      Compound of Example 135                                                        ##STR469##            R.sup.2 = H,                                                                   ##STR470##                                            Crystal form: yellow powdery (recrystallized from                             dimethylformamide-water)                                                      Mp: 182-183° C.                                                        __________________________________________________________________________

                  TABLE 9                                                         ______________________________________                                         ##STR471##                                                                   Compound of Example 136                                                       ______________________________________                                         ##STR472##    R.sup.2 = H,                                                                   ##STR473##                                                    Crystal form: light brown powdery (recrystallized                             from ethanol)                                                                 Mp: 191-192° C.                                                        ______________________________________                                    

Example 137

In 25 ml of acetic acid was dissolved 2 g of 6-2-(3,4-dimethoxybenzoyloxy)acetyl!-3,4-dihydro-carbostyril. Thereto wasadded 2 g of ammonium acetate. The mixture was stirred at 130° C. for 3hours with heating. The solvent was removed by distillation. The residuewas dissolved in ethanol. The solution was treated with active carbon,and then recrystallization was conducted to obtain 120 mg of2-(3,4-dimethoxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)oxazole as lightbrown acicular crystals.

M.p.: 191°-192° C.

Example 138

There were mixed, each in a powdery state, 500 mg of 6-2-(3,4-dimethoxybenzoylamino)acetyl!-3,4-dihydrocarbostyril and2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(Lawesson's reagent). The mixture was stirred at 200° C. with heating.After 3 hours, the reaction was completed. The residue was subjected tosilica gel column chromatography (dichloromethane:methanol=49:1 by v/v).A solid obtained from the eluate was recrystallized from ethanol toobtain 98 mg of2-(3,4-dimethoxyphenyl)-5-(3,4-dihydrocarbostyril-6-yl)thiazole as awhite powder.

M.p. 235°-236° C.

The compounds of Examples 1-95 and 97-135 were obtained by usingrespective starting materials, in the same procedure as in Example 138.

Example 139

In 50 ml of dichloromethane was dissolved 1 g of2-(pyridin-3-yl)-4-phenylthiazole. Thereto was added 900 mg ofm-chloroperbenzoic acid at room temperature. The mixture was stirred atthe same temperature for 2 hours. The reaction mixture was washed withan aqueous sodium hydrogencarbonate solution and dried. The solvent wasremoved by distillation. The residue was recrystallized from ethylacetate to obtain 306 mg of 3-(4-phenylthiazol-2-yl)pyridine-N-oxide asa brown powder.

M.p.: 140°-141° C.

Example 140

In 25 ml of acetic anhydride was dissolved 2.8 g of3-(4-phenylthiazol-2-yl)pyridine-N-oxide. The solution was refluxed for6 hours with heating. The solvent was removed by distillation. Theresidue was treated with ammonia water and extracted withdichloromethane. The extract was water-washed, dried and subjected tosolvent removal by distillation. The residue was mixed with a smallamount of dichloromethane. The resulting crystals were collected byfiltration and recrystallized from methanol to obtain 60 mg of2-(2-oxopyridin-3-yl)4-phenylthiazole as light brown plate crystals.

M.p.: 206°-207° C. (decomposed).

Example 141

In 50 ml of tetrahydrofuran was suspended 103 mg of lithium aluminumhydride. Thereto was added, in small portions, 1 g of2-(3,4-dimethoxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole. Themixture was stirred at 90° C. for 3 hours with heating. 0.3 ml of waterwas added under ice-cooling, and the mixture was stirred and thenfiltered. The residue was extracted with dichloromethane. The extractwas water-washed, dried and subjected to solvent removal bydistillation. The residue was treated with active carbon and thenconverted into a hydrochloride with methanolhydrochloric acid. Thehydrochloride was recrystallized from ethanol to obtain 465 mg of2-(3,4-dimethoxyphenyl)-4-(1,2,3,4-tetrahydroquinolin-6-yl)thiazolehydrochloride as a light brown powder.

M.p.: 156°-158° C.

Example 142

In 4 ml of acetic acid and 2 ml of hydrobromic acid was suspended 500 mgof 2-(3,4-dimethoxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole. Thesuspension was refluxed for 6 hours with heating. After cooling, theresulting crystals were collected by filtration, dried andrecrystallized from ethanol to obtain 67 mg of2-(3,4-dihydroxyphenyl)-4-(3,4-dihydrocarbostyreil-6-thiazole as ayellow powder.

M.p.: 255°-258° C. (decomposed).

Example 143

In 20 ml of DMF was dissolved 0.57 g of2-(3,4-dimethoxyphenl)-4-(3,4-dihydro-2H-1,4-benzothiazin-3(4H)-one-6-yl)thiazole.0.065 g of 60% sodium hydride was added under ice-cooling. The mixturewas stirred for 30 minutes. 0.18 ml of methyl iodide was added, and themixture was stirred at 0° C. to room temperature overnight. The solutionwas concentrated and mixed with water. The resulting crystals werecollected by filtration, water-washed and dried. The crystals wererecrystallized from DMF-water to obtain 0.32 g of2-(3,4-dimethoxyphenyl)-4-(4-methyl-2H-1,4-benzothiazin-3(4H)-one-6-yl)thiazoleas a light yellow powder.

M.p.: 143.5°-144° C.

The compounds of Examples 11, 29, 36, 42, 48, 61, 62, 71, 75, 78, 102and 123 were obtained by using respective starting materials, in thesame procedure as in Example 143.

Example 144

In 10 ml of pyridine was dissolved 1 g of2-(3,4-dimethoxyphenyl)-4-(1,2,3,4-tetrahydroquinolin-6-yl)thiazole.Thereto was added 0.44 g of benzoyl chloride at 0° C., and the mixturewas stirred for 5 hours. The solution was concentrated and mixed withethanol and water in this order. The resulting crystals were collectedby filtration and recrystallized from ethanol to obtain 0.7 g of2-(3,4-dimethoxyphenyl)-4-(1-benzoyl-1,2,3,4-tetrahydroquinolin-6-yl)thiazoleas a light yellow powder.

M.p.: 152.5°-153.5° C.

Example 145

In 20 ml of tetrahydrofuran was dissolved 300 mg of2-(3,4-dimethoxyphenyl)-4-(3-amino-4-hydroxyphenyl)thiazole. Thereto wasadded 0.46 ml of triethylamine at room temperature. The mixture wasstirred at the same temperature for 30 minutes. 100 mg of phosgene wasblown thereinto, and the resulting mixture was stirred for 2 hours. Thesolvent was distilled off. The residue was washed with diethyl ether,followed by filtration to collect crystals. The crystals wererecrystallized from methanol to obtain 50 mg of2-(3,4-dimethoxyphenyl)-4-(benzoxazol-2-on-5-yl)thiazole as a whitepowder.

M.p.: 271°-272° C.

Example 146

In 10 ml of aceticanhydride and 10 ml of pyridine was dissolved 1 g of2-(3,4-dimethoxyphenyl)-4-(1,2,3,4-tetrahydroquinolin-6-yl)thiazole. Thesolution was stirred at room temperature overnight. The reaction mixturewas concentrated. The concentrate was mixed with water. The resultingcrystals were collected by filtration, water-washed and dried.Recrystallization from ethanol was conducted to obtain 0.31 g of2-(3,4-dimethoxyphenyl)-4-(1-acetyl-1,2,3,4-tetrahydroquinolin-6-yl)thiazoleas colorless acicular crystals.

M.p.: 147.5°-148.5° C.

The compounds of Examples 57, 63, 66, 76, 77 and 81 were obtained byusing respective starting materials, in the same procedure as in Example146.

Example 147

2.05 g of2-(4-ethoxycarbonylphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole wassuspended in 20 ml of a 10% aqueous potassium hydroxide solution and 50ml of ethanol. The suspension was refluxed for 5 hours. Ethanol wasremoved by distillation. After cooling, the residue was mixed withhydrochloric acid to make it acidic (pH 1). The resulting crystals werecollected by filtration and recrystallized from dimethylformamide toobtain 0.70 g of2-(4-carboxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole as a lightyellow powder.

M.p.: 300° C. or above

Example 148

In 20 ml of oxalyl chloride was suspended 0.62 g of2-(4-carboxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole. Thesuspension was refluxed for 1 hour with heating. Oxalyl chloride wasdistilled off. The residue was suspended in acetone under ice-cooling.Thereto was added ammonia water. The mixture was returned to roomtemperature and stirred overnight. The mixture was mixed with water. Theresulting crystals were collected by filtration, water-washed, dried andrecrystallized from dimethylformamide to obtain 0.29 g of2-(4-carbamoylphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole as a lightyellow powder.

M.p.: 300° C. or above.

Example 149

In 150 ml of chloroform-ethanol was suspended 3.40 g of2-(3-methoxy-4-methylthiophenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole.Thereto was added, in small portions, 1.97 g of methachloroperbenzoicacid (80%) under ice-cooling. The mixture was stirred for 1 hour. Then,the mixture was returned to room temperature and stirred overnight.Thereto was added an aqueous sodium carbonate solution. The mixture wasextracted with chloroform three times. The combined extract was washedwith a saturated aqueous sodium chloride solution and dried overmagnesium sulfate. The solvent was distilled off and the resultingcrystals were recrystallized from dimethylformamide to obtain 0.50 g of2-(3-methoxy-4-methylsulfinylphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazoleas light yellow acicular crystals.

M.p.: 264°-265° C.

The compound of Example 45 was obtained by using the starting material,in the same procedure as in Example 149.

Example 150

In 100 ml of chloroform-ethanol was suspended 2.9 g of2-(3-methoxy-4-methylsulfinylphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole.Under ice-cooling, 1.72 g of m-chloroperbenzoic acid (80%) was added insmall portions and the mixture was stirred for 1 hour. Then, the mixturewas returned to room temperature and stirred overnight. The resultingcrystals were collected by filtration, washed with ethanol and diethylether, and dried. Recrystallization from dimethylformamide-water toobtain 0.50 g of2-(3-methoxy-4-methylsuflonylphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazoleas a white powder.

M.p.: 284°-286° C.

Example 151

In 6 ml of chloroform was dissolved 100 mg of2-(3,4-dimethoxybenzoyl)-4-(3,4-dihydroxycarbostyril-6-yl)thiazole.Thereto was added sodium boron hydride at room temperature, and themixture was stirred for 1 hour at the same temperature. The solvent wasdistilled off. The residue was extracted with chloroform. The extractwas water-washed, dried and then subjected to solvent removal bydistilation. The residue was purified by silica gel columnchromatography (eluent: chloroform/methanol=99/1) and thenrecrystallized from ethyl acetate to obtain 52 mg of 2-1-(3,4-dimethoxyphenyl)-1-hydroxymethyl!-4-(3,4-dihydroxycarbostyril-6-yl)thiazoleas light brown prismatic crystals.

M.p.: 188°-189° C.

Example 152

In 50 ml of acetic acid was suspended 2 g of2-(3,4-dimebthoxybenzyl)-3,4-dihydroxycarbostyril-6-yl)thiazole. Theretowas added 1.2 g of CrO₃. The mixture was stirred at 70°-80° C. for 3hours. Then, 2 g of activated magnesium silicate Florisil (trade name)manufactured by Wako Pure Chemical Industry, Ltd.! was added, and themixture was stirred at room temperature for 1 hour. After the completionof a reaction, the solvent was removed by distillation, and the residuewas suspended in a chloroform-methanol (4:1) mixture. The suspension wasfiltered. The filtrate was subjected to solvent removal by distillation.The residue was purified by silica gel column chromatography (eluent:chloroform/methanol=199/1) and then recrystallized fromchloroform-ethanol to obtain 300 mg of2-(3,4-dimethoxybenzoyl)-4-(3,4-dihydroxycarbostyril-6-yl)thiazole aslight brown acicular crystals.

M.p.: 249°-251° C.

Example 154-234

Compounds shown in the following Table 10 were obtained by usingrespective starting materials, in the same procedures as in Examples 1and 138.

                  TABLE 10                                                        ______________________________________                                         ##STR474##                                                                   ______________________________________                                        Compound of Example 154                                                        ##STR475##                                                                    ##STR476##                                                                   Crystal form: yellow powdery (recrystallized from                             dioxane)                                                                      Mp: 196.5-197° C. Form: free                                           Compound of Example 155                                                        ##STR477##                                                                    ##STR478##                                                                   Crystal form: light brown acicular (recrystallized                            from methanol)                                                                Mp: 133-135° C. Form: free                                             Compound of Example 156                                                        ##STR479##                                                                    ##STR480##                                                                   Crystal form: light yellow powdery (recrystallized                            from ethanol-water)                                                           Mp: 198-200° C. Form: 2 HCl salt                                       Compound of Example 157                                                        ##STR481##                                                                    ##STR482##                                                                   Crystal form: colorless acicular (recrystallized                              from dioxane)                                                                 Mp: 185-186° C. Form: free                                             Compound of Example 158                                                        ##STR483##                                                                    ##STR484##                                                                   Crystal form: white powdery (recrystallized from                              ethanol)                                                                      Mp: 121-123° C. Form: free                                             Compound of Example 159                                                        ##STR485##                                                                    ##STR486##                                                                   Crystal form: white powdery (recrystallized from                              dioxane-water)                                                                Mp: 255-256° C. Form: free                                             Compound of Example 160                                                        ##STR487##                                                                    ##STR488##                                                                   Crystal form: white powdery (recrystallized from                              dioxane)                                                                      Mp: 164-165° C. Form: free                                             Compound of Example 161                                                        ##STR489##                                                                    ##STR490##                                                                   Crystal form: colorless acicular (recrystallized                              from dioxane)                                                                 Mp: 203-204° C. Form: free                                             Compound of Example 162                                                        ##STR491##                                                                    ##STR492##                                                                   Crystal form: colorless acicular (recrystallized                              from ethanol)                                                                 Mp: 125.5-126.5° C. Form: free                                         Compound of Example 163                                                        ##STR493##                                                                    ##STR494##                                                                   Crystal form: colorless acicular (recrystallized                              from ethanol)                                                                 Mp: 170-171° C. Form: free                                             Compound of Example 164                                                        ##STR495##                                                                    ##STR496##                                                                   Crystal form: white powdery (recrystallized from                              dioxane)                                                                      Mp: 203-204° C. Form: free                                             Compound of Example 165                                                        ##STR497##                                                                    ##STR498##                                                                   Crystal form: colorless acicular (recrystallized                              from dioxane)                                                                 Mp: 179-181° C. Form: free                                             Compound of Example 166                                                        ##STR499##                                                                    ##STR500##                                                                   Crystal form: light yellow prismatic (recrystallized                          from dioxane)                                                                 Mp: 250-251° C. From: free                                             Compound of Example 167                                                        ##STR501##                                                                    ##STR502##                                                                   Crystal form: white acicular (recrystallized from                             dioxane-water)                                                                Mp: 188-189° C. Form: free                                             Compound of Example 168                                                        ##STR503##                                                                    ##STR504##                                                                   Crystal form: light yellow acicular (recrystallized                           from dioxane-water)                                                           Mp. 189-190° C. Form: free                                             Compound of Example 169                                                        ##STR505##                                                                    ##STR506##                                                                   Crystal form: light brown prismatic (recrystallized                           from ethyl acetate)                                                           Mp: 171-172° C. Form: free                                             Compound of Example 170                                                        ##STR507##                                                                    ##STR508##                                                                   Crystal form: colorless acicular (recrystallized                              from ethanol)                                                                 Mp: 125-126° C. Form: free                                             Compound of Example 171                                                        ##STR509##                                                                    ##STR510##                                                                   Crystal form: colorless acicular (recrystallized                              from ethanol)                                                                 Mp: 195-197° C. Form: free                                             Compound of Example 172                                                        ##STR511##                                                                    ##STR512##                                                                   Crystal form: light yellow powdery (recrystallized                            from ethanol-water)                                                           Mp: 96-97° C. Form: HCl salt                                           Compound of Example 173                                                        ##STR513##                                                                    ##STR514##                                                                   Crystal form: light brown powdery (recrystallized                             from ethanol)                                                                 Mp: 138-139° C. Form: dihydrochloride                                  Compound of Example 174                                                        ##STR515##                                                                    ##STR516##                                                                   Crystal form: light yellow powdery                                            Mp. 248-249° C. Form: free                                             Compound of Example 175                                                        ##STR517##                                                                    ##STR518##                                                                   Crystal form: light yellow plate (recrystallized                              from ethanol)                                                                 Mp: 195-196° C. Form: free                                             Compound of Example 176                                                        ##STR519##                                                                    ##STR520##                                                                   Crystal form: white powdery (recrystallized from                              ethyl acetate)                                                                Mp: 180-181° C. Form: free                                             Compound of Example 177                                                        ##STR521##                                                                    ##STR522##                                                                   Crystal form: light Yellow Prismatic (recrystallized                          from dioxane)                                                                 Mp: 254-255° C. Form: free                                             Compound of Example 178                                                        ##STR523##                                                                    ##STR524##                                                                   Crystal form: brown powdery (recrystallized from                              ethanol-diethyl ether)                                                        Mp: 164-165° C. Form: dihydrochloride                                  Compound of Example 179                                                        ##STR525##                                                                    ##STR526##                                                                   Crystal form: light yellow acicular (recrystallized                           from ethanol)                                                                 Mp: 138-139° C. Form: free                                             Compound of Example 180                                                        ##STR527##                                                                    ##STR528##                                                                   Crystal form: yellow acicular (recrystallized from                            ethanol)                                                                      Mp: 117-118° C. Form: dihydrochloride                                  Compound of Example 181                                                        ##STR529##                                                                    ##STR530##                                                                   Crystal form: colorless acicular (recrystallized                              from ethanol)                                                                 Mp: 168-170° C. Form: trihydrochloride                                 Compound of Example 182                                                        ##STR531##                                                                    ##STR532##                                                                   Crystal form: white prismatic (recrystallized from                            toluene)                                                                      Mp: 175-176° C. Form: free                                             Compound of Example 183                                                        ##STR533##                                                                    ##STR534##                                                                   Crystal form: white powdery (recrystallized from                              ethyl acetate-n-hexane)                                                       Mp: 180-181° C. Form: free                                             Compound of Example 184                                                        ##STR535##                                                                    ##STR536##                                                                   Crystal form: white acicular (recrystallized from                             ethanol)                                                                      Mp: 138-140° C. Form: free                                             Compound of Example 185                                                        ##STR537##                                                                    ##STR538##                                                                   Crystal form: yellow powdery (recrystallized from                             ethanol-water)                                                                Mp: 175-176° C. Form: free                                             Compound of Example 186                                                        ##STR539##                                                                    ##STR540##                                                                   Crystal form: light yellow acicular (recrystallized                           from ethanol-diethyl ether)                                                   Mp: 138-140° C. Form: hydrochloride                                    Compound of Example 187                                                        ##STR541##                                                                    ##STR542##                                                                   Crystal form: orange acicular (recrystallized from                            ethyl acetate-n-hexane)                                                       Mp: 119-120° C. Form: free                                             Compound of Example 188                                                        ##STR543##                                                                    ##STR544##                                                                   Crystal form: brown prismatic (recrystallized from                            ethanol)                                                                      Mp: 202-203° C. Form: hydrochloride                                    Compound of Example 189                                                        ##STR545##                                                                    ##STR546##                                                                   Crystal form: yellow acicular (recrystallized from                            dioxane-water)                                                                Mp: 142-143° C. From: free                                             Compound of Example 190                                                        ##STR547##                                                                    ##STR548##                                                                   Crystal form: white acicular (recrystallized from                             ethanol)                                                                      Mp: 194-195° C. Form: free                                             Compound of Example 191                                                        ##STR549##                                                                    ##STR550##                                                                   Crystal form: colorless acicular (recrystallized                              from ethanol-water)                                                           Mp: 173-175° C. Form: hydrochloride                                    Compound of Example 192                                                        ##STR551##                                                                    ##STR552##                                                                   Crystal form: light yellow acicular (recrystallized                           from ethanol)                                                                 Mp: 98-99° C. Form: free                                               Compound of Example 193                                                        ##STR553##                                                                    ##STR554##                                                                   Crystal form: colorless acicular (recrystallized                              from ethanol)                                                                 Mp: 95-96° C. Form: free                                               Compound of Example 194                                                        ##STR555##                                                                    ##STR556##                                                                   Crystal form: yellow acicular (recrystallized from                            dioxane-water)                                                                Mp: 145-146.5° C. Form: free                                           Compound of Example 195                                                        ##STR557##                                                                    ##STR558##                                                                   Crystal form: colorless acicular (recrystallized                              from ethanol)                                                                 Mp: 114-114.5° C. Form: free                                           Compound of Example 196                                                        ##STR559##                                                                    ##STR560##                                                                   Crystal form: yellow powdery (recrystallized from                             ethanol)                                                                      Mp: 158-180° C. (decomposed) Form: dihydrochloride                     NMR (DMSO-d.sub.6) δ:                                                   1.28-1.5(6H, m), 4.02-4.25(4H, m), 7.10(1H, d, J=                             8.3Hz), 7.19(1H, d, J=8.5Hz), 7.46-7.63(2H, m),                               7.83-7.97(2H, m), 8.12(1H, d, J=2Hz)                                          Compound of Example 197                                                        ##STR561##                                                                    ##STR562##                                                                   Crystal form: light green powdery (recrystallized                             from ethanol-water)                                                           Mp: 230° C. (decomposed) Form: hydrochloride                           Compound of Example 198                                                        ##STR563##                                                                    ##STR564##                                                                   Crystal form: colorless acicular (recrystallized                              from ethanol)                                                                 Mp: 244° C. (decomposed) Form: hydrochloride                           Compound of Example 199                                                        ##STR565##                                                                    ##STR566##                                                                   Crystal form: colorless acicular (recrystallized                              from ethanol)                                                                 Mp: 111-112° C. Form: free                                             Compound cf Example 200                                                        ##STR567##                                                                    ##STR568##                                                                   Crystal form: colorless column (recrystallized from                           dioxane)                                                                      Mp: 228-229° C. Form: free                                             Compound of Example 201                                                        ##STR569##                                                                    ##STR570##                                                                   Crystal form: white powdery (recrystallized from                              ethanol-water)                                                                Mp: 186-188° C. Form: dihydrochloride                                  Compound of Example 202                                                        ##STR571##                                                                    ##STR572##                                                                   Crystal form: yellow acicular (recrystallized from                            methanol-ethyl acetate)                                                       Mp: 170-171° C. Form: free                                             Compound of Example 203                                                        ##STR573##                                                                    ##STR574##                                                                   Crystal form: white powdery (recrystallized from                              ethyl acetate-n-hexane)                                                       Mp: 112-113° C. Form: free                                             Compound of Example 204                                                        ##STR575##                                                                    ##STR576##                                                                   Crystal form: white powdery (recrystallized from                              ethanol)                                                                      Mp: 150-154° C. (decomposed) Form: dihydrochloride                     Compound of Example 205                                                        ##STR577##                                                                    ##STR578##                                                                   Crystal form: white powdery (recrystallized from                              methanol-ethyl acetate)                                                       Mp. 206-208° C. Form: trihydrochloride                                 Compound of Example 206                                                        ##STR579##                                                                    ##STR580##                                                                   Crystal form: powdery (recrystallized from                                    ethanol)                                                                      Mp: 155-158° C. (decomposed) Form: trihydrochloride                    Compound of Example 207                                                        ##STR581##                                                                    ##STR582##                                                                   Crystal form: white powdery (recrystallized from                              ethanol)                                                                      Mp: 241-242° C. Form: trihydrochloride                                 Compound of Example 208                                                        ##STR583##                                                                    ##STR584##                                                                   Crystal form: yellow powdery (recrystallized from                             ethanol)                                                                      Mp: 156-162° C. dihydrochloride                                        Compound of Example 209                                                        ##STR585##                                                                    ##STR586##                                                                   NMR (DMSO-d.sub.6) δ:                                                   2.83(3H, brs), 3.28-3.82(8H, m), 3.85(3H, s),                                 3.91(3H, s), 7.11(2H, d, J=8.4Hz), 7.52-7.68                                  (2H, m), 7.87(1H, s), 7.98(1H, dd, J=2.0Hz, 8.5Hz),                           8.30(1H, d, J=2.0Hz)                                                          Crystal form: yellow powdery (recrystallized from                             ethanol)                                                                      Mp: 178-190° C. Form: trihydrochloride                                 Compound of Example 210                                                        ##STR587##                                                                    ##STR588##                                                                   Crystal form: white powdery (recrystallized from                              ethanol)                                                                      Mp: 188-192° C. (decomosed) Form: dihydrochloride                      Compound of Example 211                                                        ##STR589##                                                                    ##STR590##                                                                   Crystal form: yellow acicular (recrystallized from                            ethyl acetate-ethanol)                                                        Mp: 166-170° C. Form: trihydrochloride                                 Compound of Example 212                                                        ##STR591##                                                                    ##STR592##                                                                   Crystal form: yellow powdery (recrystallized from                             ethanol)                                                                      Mp: 167-171° C. Form: dihydrochloride                                  Compound of Example 213                                                        ##STR593##                                                                    ##STR594##                                                                   Crystal form: white acicular (recrystallized from                             ethanol)                                                                      Mp: 137-138° C. Form: free                                             Compound of Example 214                                                        ##STR595##                                                                    ##STR596##                                                                   Crystal form: colorless prismatic (recrystallized                             from ethyl acetate)                                                           Mp: 121-122° C. Form: free                                             Compound of Example 215                                                        ##STR597##                                                                    ##STR598##                                                                   Crystal form: colorless acicular (recrystallized                              from ethanol)                                                                 Mp. 176-177° C. Form: free                                             Compound of Example 216                                                        ##STR599##                                                                    ##STR600##                                                                   Crystal form: white powdery (recrystallized from                              ethanol acetate)                                                              Mp: 185-186° C. Form: hydrochloride                                    Compound of Example 217                                                        ##STR601##                                                                    ##STR602##                                                                   Crystal form: white granular (recrystallized from                             diisopropyl ether)                                                            Mp: 113-114° C. Form: free                                             Compound of Example 218                                                        ##STR603##                                                                    ##STR604##                                                                   Crystal form: white powdery (recrystallized from                              ethyl acetate)                                                                Mp: 212-214° C. Form: dihydrochloride                                  Compound of Example 219                                                        ##STR605##                                                                    ##STR606##                                                                   Crystal form: white plate (recrystallized from                                ethanol)                                                                      Mp: 126-128° C. Form: free                                             Compound of Example 220                                                        ##STR607##                                                                    ##STR608##                                                                   Crystal form: light yellow acicular (recrystallized                           from ethanol)                                                                 Mp: 97-98° C. Form: free                                               Compound of Example 221                                                        ##STR609##                                                                    ##STR610##                                                                   Crystal form: white acicular (recrystallized from                             ethanol)                                                                      Mp: 161-164° C. Form: hydrochloride                                    Compound of Example 222                                                        ##STR611##                                                                   R.sup.2 = CO.sub.2 C.sub.2 H.sub.5, R.sup.3 = CO.sub.2 C.sub.2 H.sub.5,       Crystal form: white powdery (recrystallized from                              ethyl acetate)                                                                Mp: 212-214° C. Form: dihydrochloride                                  Compound of Example 223                                                        ##STR612##                                                                    ##STR613##                                                                   Crystal form: yellow powdery (recrystallized from                             dimethylformamide)                                                            Mp: 270-279° C. (decomposed) Form: free                                NMR (DMSO-D.sub.6) δ:                                                   1.39(3H, t, J=6.8Hz), 1.40(3H, t, J=6.8Hz),                                   4.00-4.3(4H, m), 7.13(1H, d, J=8.4Hz), 7.16(1H, d,                            J=2.0Hz), 7.68(1H, dd, J=2.0Hz, 8.4Hz), 11.97(2H,                             brs)                                                                          Compound of Example 224                                                        ##STR614##                                                                    ##STR615##                                                                   Crystal form: light brown powdery (recrystallized                             from ethanol)                                                                 Mp: 188-210° C. (decomposed) Form: dihydrochloride                     NMR (DMSO-d.sub.6) δ:                                                   2.82(3H, s), 3.25-3.78(8H, m), 3.85(3H, s), 3.88                              (3H, s), 4.49(2H, brs), 7.09(1H, d, J=8.6Hz),                                 7.44-7.60(2H, m), 7.92(1H, s)                                                 Compound of Example 225                                                        ##STR616##                                                                    ##STR617##                                                                   Crystal form: yellow powdery (recrystallized                                  from acetone)                                                                 Mp: 114-115°0 C. Form: hydrochloride                                   Compound of Example 226                                                        ##STR618##                                                                    ##STR619##                                                                   Crystal form: light brown powdery (recrystallized                             from diethyl ether)                                                           Mp: 122-123° C. Form: free                                             Compound of Example 227                                                        ##STR620##                                                                    ##STR621##                                                                   Crystal form: white powdery (recrystallized from                              ethyl acetate-n-hexane)                                                       Mp: 128-129° C. Form: free                                             Compound of Example 228                                                        ##STR622##                                                                    ##STR623##                                                                   Crystal form: dark yellow powdery (recrystallized                             from dimethylformamide-water)                                                 Mp: 285-290° C. (decomposed) Form: free                                Compound of Example 229                                                        ##STR624##                                                                    ##STR625##                                                                   Crystal form: colorless prismatic (recrystallized                             from ethyl)                                                                   Mp: 130-131° C. Form: free                                             Compound of Example 230                                                        ##STR626##                                                                    ##STR627##                                                                   Crystal form: light brown powdery (recrystallized                             from dimethylformamide-ethanol)                                               Mp: 256-257° C. Form: free                                             Compound of Example 231                                                        ##STR628##                                                                    ##STR629##                                                                   Crystal form: light yellow powdery                                            Mp: 94-95° C. Form: free                                               Compound of Example 232                                                        ##STR630##                                                                    ##STR631##                                                                   Compound of Example 233                                                        ##STR632##                                                                    ##STR633##                                                                   Crystal form: colorless prismatic (recrystallized                             from methylene chloride-ehtanol)                                              Mp: 195-196° C. Form: free                                             Compound of Example 234                                                        ##STR634##                                                                    ##STR635##                                                                   ______________________________________                                    

Example 235

5.9 g of 4-(3,5-dinitrophenyl)-2-(3,4-dimethoxyphenyl)triazole and asolution of 24.4 g of stannous chloride dihydrate dissolved in 90 ml ofconcentrated hydrochloric acid were stirred at room temperature for 2hours. After cooling, the resulting crystals were collected byfiltration and recrystallized from ethanol-water to obtain 3.73 g of4-(3,5-diaminophenyl)-2-(3,4-dimethoxyphenyl)thiazole dihydrochloride.

M.p.: 198°-200° C., Light yellow powder.

The compounds of Examples 55, 91, 104, 181, 191, 196, 197, 198, 208 and232 were obtained using respective starting materials, in the sameprocedure as in Example 235.

Example 236

In 45 ml of tetrahydrofuran were dissolved 1.5 g of4-(4-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole, 1.4 g of2,3,4,6-tetra-O-acetyl-β-D-glucopyranose and 1.3 g oftriphenylphosphine. Thereto was added, in small portions at 0° C., asolution of 0.9 g of diethyl azodicarboxylate dissolved in 5 ml oftetrahydrofuran. The mixture was stirred at room temperature for 14hours. The solvent was removed by distillation. The residue was purifiedby silica gel column chromatography (elutant: dichloromethane) andrecrystallized from ethyl acetate-n-hexane to obtain 1.52 g of 4-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)phenyl!-2-(3,4-diethoxyphenyl)thiazole.

M.p.: 180°-181° C., White powder

The compounds of Examples 171 and 184 were obtained using respectivestarting materials, in the same procedure as in Example 236.

Example 237

In 6 ml of a methanol-dichloromethane (2:1) mixed solvent was suspended0.15 g of 4-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)phenyl!-2-(3,4-diethoxyphenyl)thiazole.Thereto was added a catalytic amount of sodium methylate. The mixturewas stirred at room temperature for 2 hours. The solvent was removed bydistillation. The residue was recrystallized from methanol to obtain 71mg of 4-4-(β-D-glucopyranosyloxy)phenyl!-2-(3,4-diethoxyphenyl)thiazole.

M.p.: 138°-140° C., White acicular crystals

Example 238

2 ml of chlorosulfonic acid was dropwise added to 40 ml of pyridine atroom temperature. The mixture was stirred at 50° C. for 12 hours.Thereto was added 0.33 g of4-(4-hydroxyphenyl-2-(3,4-dimethoxyphenyl)thiazole. The mixture wasstirred at 50° C. for 6 hours and then at room temperature overnight.The reaction mixture was concentrated to dryness under reduced pressure.The residue was mixed with water and the resulting crystals werecollected by filtration. The resulting4-(4-hydroxysulfonyloxyphenyl)-2-(3,4-dimethoxyphenyl)thiazolepyridinium salt was suspended in 3 ml of methanol. Thereto was added 5ml of a 0.1N aqueous potassium hydroxide solution. The mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated. The residue was dissolved in water. The solution wastreated with 0.5 g of an ion exchange resin (Dowex 50Wx8). The filtratewas concentrated to obtain 0.04 g of4-(4-hydroxysulfonyloxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole.

M.p.: 248°-249° C., Light yellow powder.

Example 239

In 25 ml of ethanol were suspended 0.5 g of4-(4-hydroxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole, 1 g ofparaformaldehyde and 0.5 g of N-methylpiperazine. The suspension wasrefluxed for 8 hours with heating. The reaction mixture was subjected todistillation under reduced pressure to remove the solvent. The residuewas purified by silica gel column chromatography (eluent:dichloromethane/methanol=49/1 by v/v) and dissolved in 10 ml of ethanol.Thereto was added 0.5 ml of ethanol saturated with hydrogen chloridegas, and the mixture was allowed to stand. The resulting crystals werecollected by filtration, dried and recrystallized from ethanol to obtain0.2 g of 4-4-hydroxy-3-(4-methyl-1-piperazinylmethyl)phenyl!-2-(3,4-dimethoxyphenyl)thiazoletrihydrochloride.

M.p.: 178°-190° C., Yellow powder, NMR (DMSO-d₆) δ: 2.83-3.82 (3H, brs),3.28-3.82 (8H, m), 3.85 (3H, s), 3.91 (3H, s), 7.11 (2H, d, J=8.4 Hz),7.52-7.68 (2H, m), 7.87 (1H, s), 7.98 (1H, dd, J=2.0 Hz, 8.5 Hz), 8.30(1H, d, J=2.0 Hz).

Example 240

20 ml of a dimethylformamide solution containing 1.5 g of4-(3-methoxy-5-carboxyphenyl)-2-(3,4-diethoxyphenyl)thiazole, 0.4 g ofN-methylpiperazine and 0.7 g of diethyl cyanophosphonate was stirredwith ice-cooling. Thereto was added 0.6 ml of triethylamine. The mixturewas stirred at room temperature for 14 hours. The solvent was distilledoff. The residue was mixed with 80 ml of dichloromethane and 30 ml ofwater. Phase separation was conducted and the dichloromethane layer waswashed with 20 ml of a saturated aqueous sodium hydrogencarbonatesolution was 20 ml of a saturated aqueous sodium chloride solution, anddried. The solvent was removed by distillation. The residue was purifiedby silica gel column chromatography (eluent:dichloromethane/methanol=200/3 by v/v) and then dissolved in ethylacetate. To the solution was added hydrochloric acid-ethanol. Theresulting crystals were collected by filtration, dried andrecrystallized from ethyl acetate to obtain 1.2 g of 4-3-methoxy-5-(4-methyl-1-piperzinylcarbonyl)phenyl!-2-(3,4-diethoxyphenyl)thiazolehydrochloride.

White powder, M.p.: 185°-186° C.

The compounds of Examples 120, 217 and 233 were obtained by usingrespective starting materials, in the same procedure as in Example 240.

Example 241

In 20 ml of tetrahydrofuran was dissolved 0.4 g of 4-3-methoxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl-2-(3,4-diethoxyphenyl)thiazole.Thereto was added 32 mg of lithium aluminum hydride in small portions.The mixture was stirred at 0° C. for 30 minutes and at room temperaturefor 2 hours. Then, there were added 0.05 ml of a 10% aqueous sodiumhydroxide solution and 0.1 ml of water. The mixture was stirred at roomtemperature for 20 minutes. The reaction mixture was filtered. Thefiltrate was concentrated. The residue was purified by silica gel columnchromatography (eluent: dichloromethane/methanol=99/1 by v/v) anddissolved in ethyl acetate. Thereto was added hydrochloric acid-ethanol.The resulting crystals were collected by filtration, dried andrecrystallized from ethyl acetate to obtain 40 mg of 4-3-methoxy-5-(4-methyl-1-piperazinylmethyl)phenyl!-2-(3,4-diethoxyphenyl)thiazoledihydrochloride.

White powder, M.p.: 212°-214° C.

The compound of Example 209 was obtained by using starting materials, inthe same procedure as in Example 241.

Example 242

A solution of 1 g of4-(4-chloro-3-nitrophenyl)-2-(3,4-diethoxyphenyl)thiazole and 636 mg ofmorpholine dissolved in 20 ml of dimethylformamide and 20 ml of dimethylsulfoxide was refluxed at 150° C. for 2-3.5 hours with heating. Thereaction mixture was subjected to vacuum distillation. The residue wasadded to ice water, and an aqueous sodium hydrogencarbonate solution wasadded. The solution was extracted with dichloromethane three times. Thecombined extract was washed with an aqueous sodium chloride solution anddried over magnesium sulfate. The solvent was removed by distillation.The residue was purified by silica gel column chromatography andrecrystallized from ethyl acetate-n-hexane to obtain 1.03 g of4-(4-morpholino-3-nitrophenyl)-2-(3,4-diethoxyphenyl)thiazole.

Orange acicular crystals, M.p.: 119°-120° C.

The compounds of Examples 173, 180, 188 and 189 were obtained by usingrespective starting materials, in the same procedure as in Example 242.

Example 243

In 4 ml of ethanol was suspended 1 g of4,5-diethoxycarbonyl-2-(3,4-diethoxyphenyl)thiazole. Thereto was added 2ml of hydrazine hydrate. The mixture was sealed in a tube and heated at130° C. for 48 hours. After cooling, the resulting crystals werecollected by filtration, washed with ethanol, dried and recrystallizedfrom dimethylformamide to obtain 220 mg of2-(3,4-diethoxyphenyl)-5,6-dihydrothiazolo 4,5-d!pyridazine-4,7-dione.

M.p.: 270°-279° C. (decomposed), Yellow powder, NMR (DMSO-d₆) δ: 1.39(3H, t, J=6.8 Hz), 1.40 (3H, t, J=6.8 Hz), 4.00-4.35 (4H, m), 7.13 (1H,d, J=8.4 Hz), 7.61 (1H, d, J=2.0 Hz), 7.68 (1H, dd, J=2.0 Hz, 8.4 Hz),11.97 (2H, brs).

Example 244

In 10 ml of dimethylformamide were dissolved 860 mg of2-(3,4-dimethoxyphenyl)-4-chloromethylthiazole and 320 mg ofN-methylpiperazine. Thereto was added 130 mg of sodium hydride. Themixture was stirred at room temperature for 14 hours. The solvent wasremoved by distillation. The residue was extracted with chloroform. Theextract was water-washed, dried and subjected to distillation to removethe solvent. The residue was dissolved in ethanol. To the solution wasadded ethanol saturated with hydrogen chloride gas, and the mixture wasallowed to stand. The resulting crystals were collected by filtration,washed with a small amount of ethanol, dried and recrystallized fromethanol to obtain 820 mg of2-(3,4-dimethoxyphenyl)-4-(4-methylpiperazinylmethyl)thiazole.

M.p.: 188°-210° C. (decomposed), Light brown powder.

The compounds of Examples 209, 212 and 218 were obtained by usingrespective starting materials, in the same procedure as in Example 244.

Example 245

60 ml of a tetrahydrofuran solution of a Grignard reagent prepared from2.4 g of 1-bromo-3,4-dimethoxybenzene was stirred with ice-cooling.Thereto was added 20 ml of a tetrahydrofuran solution of 3 g of2-(3,4-diethoxyphenyl)-4-formylthiazole. The mixture was stirred at thesame temperature for 1 hour and at room temperature for 3 hours. 10 mlof a saturated aqueous ammonium chloride solution was added. The solventwas removed by distillation. The residue was extracted with 100 ml ofchloroform. The extract was washed with 20 ml of water and 20 ml of asaturated aqueous sodium chloride solution, and dried. The solvent wasremoved by distillation. The residue was purified by silica gel columnchromatography (elutant: dichloromethane/acetone=99/1 by v/v) andrecrystallized from diethyl ether to obtain 2.2 g of2-(3,4-diethoxyphenyl)-4-1-hydroxy-1-(3,4-dimethoxyphenyl)methyl!thiazole

M.p.: 122°-123° C., Light brown powder.

The compound of Example 128 was obtained by using starting materials, inthe same procedure as in Example 245.

Example 246

In 20 ml of chloroform was dissolved 150 mg of 2-(3,4-diethoxyphenyl)-4-1-hydroxy-1-(3,4-dimethoxyphenyl)methyl!thiazole. 1 g of manganesedioxide was added. The mixture was refluxed for 2 hours with heating.The reaction mixture was filtered. The filtrate was concentrated. Theresidue was recrystallized from ethyl acetate-n-hexane to obtain 98 mg2-(3,4-diethoxyphenyl)-4-(3,4-diethoxybenzoyl)thiazole.

M.p.: 128°-129° C., White powder.

The compound of Example 127 was obtained by using starting materials, inthe same procedure as in Example 246.

Example 247

4.2 ml of n-butyllithium was dropwise added in small portions to asuspension of 2.6 g of benzyltriphenylphosphonium chloride in 10 ml oftetrahydrofuran, with stirring at -50° C. The mixture was heated to roomtemperature and, after cooling again to -50° C., was mixed with 12 ml ofa tetrahydrofuran solution of 2 g of2-(3,4-diethoxyphenyl)-4-formylthiazole. The mixture was stirred at thesame temperature for 30 minutes and at room temperature for 14 hours. 10ml of water and 40 ml of ethyl acetate were added to conduct extractionand phase separation. The solvent layer was dried and subjected todistillation to remove the solvent. The residue was purified by silicagel column chromatography to obtain 2 g of2-(3,4-diethoxyphenyl)-4-styrylthiazole as a 1:1 mixture of cis form andtrans form.

M.p.: 94°-95° C., Light yellow powder.

The compounds of Examples 129 and 135 were obtained by using respectivestarting materials, in the same procedure as in Example 247.

Example 248

The compounds of Examples 155, 169, 175, 182, 190, 196, 201, 208, 209,210, 211, 219, 220, 228 and 233 were obtained by using respectivestarting materials, in the same procedure as in Example 142.

Example 249

The compounds of Examples 172, 178, 180, 181, 186, 201, 206, 207, 209,210, 211, 216 and 234 were obtained by using respective startingmaterials, in the same procedure as in Example 143.

Example 250

The compound of Example 226 was obtained by using starting materials, inthe same procedure as in Example 151.

Example 251

The compound of Example 227 was obtained by using starting materials, inthe same procedure as in Example 152.

Example 252

The compounds of Examples 159, 175, 186, 202 and 203 were obtained byusing respective starting materials, in the same procedure as in Example146.

Examples 253-351

The compounds shown in the following Table 11 were obtained by usingrespective starting materials, in the same procedures as in Examples 1and 138.

                  TABLE 11                                                        ______________________________________                                         ##STR636##                                                                   ______________________________________                                        Compound of Example 253                                                        ##STR637##                                                                    ##STR638##                                                                   Crystal form: white powdery (recrystallized from methanol-chloroform          M.p.: 219.3-220.3° C.   Form: free                                     Compound of Example 254                                                        ##STR639##                                                                    ##STR640##                                                                   Crystal form: white acicular (recrystallized from ethanol)                    M.p.: 137-138° C.   Form: free                                         Compound of Example 255                                                        ##STR641##                                                                    ##STR642##                                                                   Crystal form: colorless acicular (recrystallized from diisopropyl ether)      M.p.: 96-97° C.   Form: free                                           Compound of Example 256                                                        ##STR643##                                                                    ##STR644##                                                                   Crystal form: white powdery (recrystallized from diisopropyl ether)           M.p.: 86-87° C.   Form: free                                           Compound of Example 257                                                        ##STR645##                                                                    ##STR646##                                                                   Crystal form: light brown granular (recrystallized from diisopropyl           ether)                                                                        M.p.: 199-200° C.   Form: free                                         Compound of Example 258                                                        ##STR647##                                                                    ##STR648##                                                                   Crystal form: colorless prismatic (recrystallized from dichloromethane-       ethanol)                                                                      M.p.: 195-196° C.   Form: free                                         Compound of Example 259                                                        ##STR649##                                                                    ##STR650##                                                                   Crystal form: white powdery (recrystallized from diethyl ether-n-hexane)      M.p.: 131-131.8° C.   Form: free                                       Compound of Example 260                                                        ##STR651##                                                                    ##STR652##                                                                   Crystal form: colorless prismatic (recrystallized from diisopropyl            ether)                                                                        M.p.: 118-119° C.   Form: free                                         Compound of Example 261                                                        ##STR653##                                                                    ##STR654##                                                                   Crystal form: white acicular (recrystallized from ethyl acetate)              M.p.: 159-160° C.   Form: free                                         Compound of Example 262                                                        ##STR655##                                                                    ##STR656##                                                                   Crystal form: white acicular (recrystallized from ethanol)                    M.p.: 156-157° C.   Form: free                                         Compound of Example 263                                                        ##STR657##                                                                    ##STR658##                                                                   Crystal form: light brown powdery (recrystallized from dioxane-ethanol)       M.p.: 283-285° C.   Form: free                                         Compound of Example 264                                                        ##STR659##                                                                    ##STR660##                                                                   Crystal form: yellow acicular (recrystallized from dichloromethane-ethanol    M.p.: 194-195° C.   Form: free                                         Compound of Example 265                                                        ##STR661##                                                                    ##STR662##                                                                   Crystal form: yellow powdery (recrystallized from ethanol-chloroform)         M.p.: 150.4-152° C.   Form: free                                       Compound of Example 266                                                        ##STR663##                                                                    ##STR664##                                                                   Crystal form: white acicular (recrystallized from ethanol)                    M.p.: 82-83° C.   Form: free                                           Compound of Example 267                                                        ##STR665##                                                                    ##STR666##                                                                   Crystal form: white acicular (recrystallized from ethyl acetate)              M.p.: 134-135° C.   Form: free                                         Compound of Example 268                                                        ##STR667##                                                                    ##STR668##                                                                   Crystal form: white acicular (recrystallized from methanol)                   M.p.: 139.8-141° C.   Form: free                                       Compound of Example 269                                                        ##STR669##                                                                    ##STR670##                                                                   Crystal form: brown powdery (recrystallized from methanol)                    M.p.: 247-248° C.   Form: free                                         Compound of Example 270                                                        ##STR671##                                                                    ##STR672##                                                                   Crystal form: white powdery (recrystallized from diethyl ether-n-hexane)      M.p.: 95.8-97.4° C.   Form: free                                       Compound of Example 271                                                        ##STR673##                                                                    ##STR674##                                                                   Crystal form: white powdery (recrystallized from methanol-chloroform)         M.p.: 248-258° C.   Form: dihydrochloride                              Compound of Example 272                                                        ##STR675##                                                                    ##STR676##                                                                   Crystal form: light yellow acicular (recrystallized from methanol)            M.p.: 116.6-118.2° C.   Form: free                                     Compound of Example 273                                                        ##STR677##                                                                    ##STR678##                                                                   Crystal form: white acicular (recrystallized from ethanol)                    M.p.: 128.6-129.2° C.   Form: free                                     Compound of Example 274                                                        ##STR679##                                                                    ##STR680##                                                                   Crystal form: white prismatic (recrystallized from ethanol)                   M.p.: 128.2-129° C.   Form: free                                       Compound of Example 275                                                        ##STR681##                                                                    ##STR682##                                                                   Crystal form: light brown granular (recrystallized from ethyl                 acetate-n-hexane)                                                             M.p.: 164-165° C.   Form: free                                         Compound of Example 276                                                        ##STR683##                                                                    ##STR684##                                                                   Crystal form: white acicular (recrystallized from ethyl acetate)              M.p.: 197-198° C.   Form: free                                         Compound of Example 277                                                        ##STR685##                                                                    ##STR686##                                                                   Crystal form: white acicular (recrystallized from ethyl                       acetate-n-hexane)                                                             M.p.: 184-185° C.   Form: free                                         Compound of Example 278                                                        ##STR687##                                                                    ##STR688##                                                                   Crystal form: white acicular (recrystallized from ethyl acetate)              M.p.: 211-212° C.   Form: free                                         Compound of Example 279                                                        ##STR689##                                                                    ##STR690##                                                                   Crystal form: white prismatic (recrystallized from toluene-diethyl            ether)                                                                        M.p.: 100.6-101.4° C.   Form: free                                     Compound of Example 280                                                        ##STR691##                                                                    ##STR692##                                                                   Crystal form: light brown powdery (recrystallized from ethanol-chloroform)    N                                                                             M.p.: 138.6-140.6° C.   Form: free                                     Compound of Example 281                                                        ##STR693##                                                                    ##STR694##                                                                   Crystal form: light pink acicular (recrystallized from ethanol)               M.p.: 192-192.8° C.   Form: free                                       Compound of Example 282                                                        ##STR695##                                                                    ##STR696##                                                                   Crystal form: white powdery (recrystallized from ethanol)                     M.p.: 208.6-211.6° C.   Form: free                                     Compound of Example 283                                                        ##STR697##                                                                    ##STR698##                                                                   Crystal form: white acicular (recrystallized from methanol)                   M.p.: 135-136° C.   Form: free                                         Compound of Example 284                                                        ##STR699##                                                                    ##STR700##                                                                   Crystal form: white powdery (recrystallized from ethanol)                     M.p.: 179-180° C.   Form: free                                         Compound of Example 285                                                        ##STR701##                                                                    ##STR702##                                                                   Crystal form: white powdery (recrystallized from ethanol)                     M.p.: 215-216° C.   Form: free                                         Compound of Example 286                                                        ##STR703##                                                                    ##STR704##                                                                   Crystal form: light green acicular (recrystallized from methanol)             M.p.: 194-196° C.   Form: free                                         Compound of Example 287                                                        ##STR705##                                                                    ##STR706##                                                                   Crystal form: white powdery (recrystallized from dioxane)                     M.p.: 272-273° C.   Form: free                                         Compound of Example 288                                                        ##STR707##                                                                    ##STR708##                                                                   Crystal form: white powdery (recrystallized from ethanol)                     M.p.: 140.2-141.6° C.   Form: free                                     Compound of Example 289                                                        ##STR709##                                                                    ##STR710##                                                                   Crystal form: white powdery (recrystallized from ethanol)                     M.p.: 177.6-178.8° C.   Form: free                                     Compound of Example 290                                                        ##STR711##                                                                    ##STR712##                                                                   Crystal form: white acicular (recrystallized from ethanol)                    M.p.: 201.5-203.4° C.   Form: free                                     Compound of Example 291                                                        ##STR713##                                                                    ##STR714##                                                                   Crystal form: white powdery (recrystallized from ethanol)                     M.p.: 120.2-121.6° C.   Form: free                                     Compound of Example 292                                                        ##STR715##                                                                    ##STR716##                                                                   Crystal form: gray acicular (recrystallized from ethanol)                     M.p.: 224.5-226.5° C.   Form: free                                     Compound of Example 293                                                        ##STR717##                                                                    ##STR718##                                                                   Crystal form: white powdery (recrystallized from ethanol)                     M.p.: 176-176.6° C.   Form: free                                       Compound of Example 294                                                        ##STR719##                                                                    ##STR720##                                                                   Crystal form: white powdery (recrystallized from ethanol)                     M.p.: 168.4-168.6° C.   Form: free                                     Compound of Example 295                                                        ##STR721##                                                                    ##STR722##                                                                   Crystal form: white acicular (recrystallized from methanol)                   M.p.: 180-181° C.   Form: free                                         Compound of Example 296                                                        ##STR723##                                                                    ##STR724##                                                                   Crystal form: white powdery (recrystallized from ethyl acetate)               M.p.: 271-273° C.   Form: free                                         Compound of Example 297                                                        ##STR725##                                                                    ##STR726##                                                                   Crystal form: light yellow powdery (recrystallized from ethyl acetate)        M.p.: 170-171° C.   Form: free                                         Compound of Example 298                                                        ##STR727##                                                                    ##STR728##                                                                   Crystal form: dark yellow powdery (recrystallized from ethanol-ethyl          acetate)                                                                      M.p.: 239-243° C. (decomposed)   Form: free                            Compound of Example 299                                                        ##STR729##                                                                    ##STR730##                                                                   Crystal form: white acicular (recrystallized from ethyl acetate)              M.p.: 199-200° C.   Form: free                                         Compound of Example 300                                                        ##STR731##                                                                    ##STR732##                                                                   Crystal form: yellow acicular (recrystallized from ethyl acetate)             M.p.: 228-229° C.   Form: free                                         Compound of Example 301                                                        ##STR733##                                                                    ##STR734##                                                                   Crystal form: white acicular (recrystallized from ethyl acetate)              M.p.: 178-179° C. (decomposed)   Form: free                            Compound of Example 302                                                        ##STR735##                                                                    ##STR736##                                                                   Crystal form: yellow acicular (recrystallized from ethyl                      acetate-n-hexane)                                                             M.p.: 138-140° C.   Form: free                                         Compound of Example 303                                                        ##STR737##                                                                    ##STR738##                                                                   Crystal form: light yellow powdery (recrystallized from ethanol)              M.p.: 203.2-203.8° C.   Form: free                                     Compound of Example 304                                                        ##STR739##                                                                    ##STR740##                                                                   Crystal form: white acicular (recrystallized from ethyl acetate)              M.p.: 252-253° C.   Form: free                                         Compound of Example 305                                                        ##STR741##                                                                    ##STR742##                                                                   Form: free                                                                    NMR: 54)                                                                      Compound of Example 306                                                        ##STR743##                                                                    ##STR744##                                                                   Crystal form: light brown plate (recrystallized from ethyl acetate)           M.p.: 233-234° C.   Form: free                                         Compound of Example 307                                                        ##STR745##                                                                    ##STR746##                                                                   Crystal form: light brown powdery (recrystallized from ethanol)               M.p.: 185.8-187° C.   Form: free                                       Compound of Example 308                                                        ##STR747##                                                                    ##STR748##                                                                   Crystal form: yellow powdery (recrystallized from ethanol-n-hexane-water)     N                                                                             M.p.: 239-240.4° C.   Form: free                                       Compound of Example 309                                                        ##STR749##                                                                    ##STR750##                                                                   Form: free                                                                    NMR: 55)                                                                      Compound of Example 310                                                        ##STR751##                                                                    ##STR752##                                                                   Crystal form: light yellow acicular (recrystallized from methanol)            M.p.: 132.8-134° C.   Form: free                                       Compound of Example 311                                                        ##STR753##                                                                    ##STR754##                                                                   Crystal form: white acicular (recrystallized from ethyl acetate)              M.p.: 92.8-94° C.   Form: free                                         Compound of Example 312                                                        ##STR755##                                                                    ##STR756##                                                                   Crystal form: white powdery (recrystallized from ethyl acetate)               M.p.: 237.4-238.5° C.   Form: free                                     Compound of Example 313                                                        ##STR757##                                                                    ##STR758##                                                                   Crystal form: white acicular (recrystallized from ethanol)                    M.p.: 151.8-152.5° C.   Form: free                                     Compound of Example 314                                                        ##STR759##                                                                    ##STR760##                                                                   Crystal form: white powdery (recrystallized from ethanol)                     M.p.: 194-195.2° C.   Form: free                                       Compound of Example 315                                                        ##STR761##                                                                    ##STR762##                                                                   Crystal form: light brown powdery (recrystallized from acetic acid)           M.p.: 252.8-253.8° C.   Form: free                                     Compound of Example 316                                                        ##STR763##                                                                    ##STR764##                                                                   Crystal form: white powdery (recrystallized from ethanol)                     M.p.: 251.6-252° C.   Form: free                                       Compound of Example 317                                                        ##STR765##                                                                    ##STR766##                                                                   Crystal form: yellow powdery (recrystallized from ethanol)                    M.p.: 230-234.5° C.   Form: free                                       Compound of Example 318                                                        ##STR767##                                                                    ##STR768##                                                                   Crystal form: white powdery (recrystallized from dioxane)                     M.p.: 270-271° C.   Form: free                                         Compound of Example 319                                                        ##STR769##                                                                    ##STR770##                                                                   Crystal form: yellow powdery (recrystallized from acetone)                    M.p.: 163-168° C.   Form: dihydrochloride                              Compound of Example 320                                                        ##STR771##                                                                    ##STR772##                                                                   Crystal form: gray powdery (recrystallized from ethanol)                      M.p.: 264-266° C.   Form: hydrochloride                                Compound of Example 321                                                        ##STR773##                                                                    ##STR774##                                                                   Crystal form: white powdery (recrystallized from methanol)                    M.p.: 170-171° C.   Form: free                                         Compound of Example 322                                                        ##STR775##                                                                    ##STR776##                                                                   Form: free                                                                    NMR: 31)                                                                      Compound of Example 323                                                        ##STR777##                                                                    ##STR778##                                                                   Crystal form: yellow powdery (recrystallized from ethanol)                    M.p.: 108-109° C.   Form: free                                         Compound of Example 324                                                        ##STR779##                                                                    ##STR780##                                                                   Form: free                                                                    NMR: 32)                                                                      Compound of Example 325                                                        ##STR781##                                                                    ##STR782##                                                                   Form: free                                                                    NMR: 33)                                                                      Compound of Example 326                                                        ##STR783##                                                                    ##STR784##                                                                   Crystal form: light brown acicular (recrystallized from diethyl ether)        M.p.: 113-114° C.   Form: free                                         Compound of Example 327                                                        ##STR785##                                                                    ##STR786##                                                                   Form: free                                                                    NMR: 34)                                                                      Compound of Example 328                                                        ##STR787##                                                                    ##STR788##                                                                   Crystal form: white acicular (recrystallized from dichloromethane-ethanol)    N                                                                             M.p.: 139-140° C.   Form: free                                         Compound of Example 329                                                        ##STR789##                                                                    ##STR790##                                                                   Form: hydrochloride                                                           NMR: 35)                                                                      Compound of Example 330                                                        ##STR791##                                                                    ##STR792##                                                                   Form: free                                                                    NMR: 36)                                                                      Compound of Example 331                                                        ##STR793##                                                                    ##STR794##                                                                   Form: free                                                                    NMR: 37)                                                                      Compound of Example 332                                                        ##STR795##                                                                    ##STR796##                                                                   Form: free                                                                    NMR: 38)                                                                      Compound of Example 333                                                        ##STR797##                                                                    ##STR798##                                                                   Form: free                                                                    NMR: 39)                                                                      Compound of Example 334                                                        ##STR799##                                                                    ##STR800##                                                                   Form: free                                                                    NMR: 40)                                                                      Compound of Example 335                                                        ##STR801##                                                                    ##STR802##                                                                   Form: free                                                                    NMR: 41)                                                                      Compound of Example 336                                                        ##STR803##                                                                    ##STR804##                                                                   Form: free                                                                    NMR: 42)                                                                      Compound of Example 337                                                        ##STR805##                                                                    ##STR806##                                                                   Form: free                                                                    NMR: 43)                                                                      Compound of Example 338                                                        ##STR807##                                                                    ##STR808##                                                                   Form: free                                                                    NMR: 44)                                                                      Compound of Example 339                                                        ##STR809##                                                                    ##STR810##                                                                   Form: free                                                                    NMR: 45)                                                                      Compound of Example 340                                                        ##STR811##                                                                    ##STR812##                                                                   Form: free                                                                    NMR: 46)                                                                      Compound of Example 341                                                        ##STR813##                                                                    ##STR814##                                                                   Form: free                                                                    NMR: 47)                                                                      Compound of Example 342                                                        ##STR815##                                                                    ##STR816##                                                                   Form: free                                                                    NMR: 48)                                                                      Compound of Example 343                                                        ##STR817##                                                                    ##STR818##                                                                   Crystal form: white acicular (recrystallized from ethanol)                    M.p.: 103-104° C.   Form: free                                         Compound of Example 344                                                        ##STR819##                                                                    ##STR820##                                                                   Crystal form: colorless amorphous   Form: free                                NMR: 50)                                                                      Compound of Example 345                                                        ##STR821##                                                                    ##STR822##                                                                   Form: free                                                                    NMR: 50)                                                                      Compound of Example 346                                                        ##STR823##                                                                    ##STR824##                                                                   Form: free                                                                    NMR: 51)                                                                      Compound of Example 347                                                        ##STR825##                                                                    ##STR826##                                                                   Form: free                                                                    NMR: 52)                                                                      Compound of Example 348                                                        ##STR827##                                                                    ##STR828##                                                                   Crystal form: white powdery (recrystallized from ethanol)                     M.p.: 85-86° C.   Form: free                                           Compound of Example 349                                                        ##STR829##                                                                    ##STR830##                                                                   Crystal form: white powdery (recrystallized from ethanol)                     M.p.: 178-179° C.                                                      Compound of Example 350                                                        ##STR831##                                                                    ##STR832##                                                                   Crystal form: light brown plate (recrystallized from ethanol)                 M.p.: 149-150° C.   Form: free                                         Compound of Example 351                                                        ##STR833##                                                                    ##STR834##                                                                   Form: free                                                                    NMR: 53)                                                                      ______________________________________                                    

NMR data of the compounds of Examples 305, 309, 322, 324, 325, 327,329-342, 344-347 and 351

NMR: 31) Compound of Example 322: NMR (CDCl₃) δ: 1.49 (3H, t, J=5.6 Hz),1.52 (3H, t, J=5.6 Hz), 3.08 (3H, s), 3.43 (3H, s), 3.49 (3H, s), 3.67(3H, s), 4.10-4.30 (4H, m), 6.92 (1H, d, J=6.7 Hz), 7.11 (1H, d, J=6.7Hz), 7.47 (1H, s), 7.52 (1H, dd, J=1.7 Hz, 6.7 Hz), 7.61 (1H, d, J=1.7Hz), 8.20 (1H, dd, J=1.8 Hz, 6.4 Hz), 8.56 (1H, d, J=1.8 Hz).

NMR: 32) Compound of Example 324: NMR (CDCl₃) δ: 1.50 (3H, t, J=6.9 Hz),1.52 (3H, t, J=6.9 Hz), 2.25-2.40 (1H, m), 2.59 (1H, d, J=5.3 Hz),2.86-3.14 (2H, m), 3.45-3.80 (2H, m), 4.01 (3H, s), 4.01 (1H, brs),4.10-4.30 (4H, m), 6.93 (1H, d, J=8.3 Hz), 7.32 (1H, s), 7.54 (1H, dd,J=2.1 Hz, 8.3 Hz), 7.59 (1H, d, J=2.1 Hz), 8.02 (1H, d, J=2.2 Hz), 8.34(1H, d, J=2.2 Hz), 11.40 (1H, s).

NMR: 33) Compound of Example 325: NMR (CDCl₃) δ: 1.50 (3H, t, J=7.0 Hz),1.52 (3H, t, J=7.0 Hz), 3.82 (2H, d, J=1.8 Hz), 4.01 (3H, s), 4.10-4.30(4H, m), 6.92 (1H, d, J=8.4 Hz), 7.33 (1H, s), 7.54 (1H, dd, J=2.1 Hz,8.4 Hz), 7.59 (1H, d, J=2.1 Hz), 8.02 (1H, d, J=2.2 Hz), 8.39 (1H, d,J=2.2 Hz), 9.81 (1H, t, J=1.8 Hz), 11.20 (1H, s).

NMR: 34) Compound of Example 327: NMR (CDCl₃) δ: 1.40-1.60 (9H, m), 2.26(3H, s), 4.16 (2H, q, J=7.0 Hz), 4.23 (2H, q, J=7.0 Hz), 4.44 (2H, q,J=7.1 Hz), 6.93 (1H, d, J=8.4 Hz), 7.40 (1H, s), 7.54 (1H, dd, J=2.1 Hz,8.4 Hz), 7.64 (1H, d, J=2.1 Hz), 8.14 (1H, dd, J=2.2 Hz, 8.8 Hz), 8.66(1H, d, J=2.2 Hz), 8.80 (1H, d, J=8.8 Hz), 11.20 (1H, s).

NMR: Compound of Example 329: NMR (DMSO-d₆) δ: 3.97 (3H, s), 6.82 (1H,d, J=8.2 Hz), 7.16 (1H, d, J=8.9 Hz), 7.32 (1H, dd, J=2.1 Hz, 8.2 Hz),7.47 (1H, d, J=2.1 Hz), 7.80 (1H, s), 8.11 (1H, dd, J=2.4 Hz, 8.9 Hz),8.38 (1H, d, J=2.4 Hz), 10.85 (1H, brs).

NMR: 36) Compound of Example 330: NMR (CDCl₃) δ: 1.35-1.60 (6H, m), 3.94(3H, s), 4.10-4.30 (4H, m), 5.73 (1H, s), 6.90 (1H, d, J=8.3 Hz), 7.03(1H, d, J=8.8 Hz), 7.30 (1H, s), 7.48-7.65 (2H, m), 8.13 (1H, dd, J=2.3Hz, 8.8 Hz), 8.41 (1H, d, J=2.3 Hz).

NMR: 37) Compound of Example 331: NMR (CDCl₃) δ: 1.46 (6H, t, J=7.0 Hz),3.92 (3H, s), 4.07-4.21 (4H, m), 6.90 (1H, d, J=8.4 Hz), 7.15 (1H, brs),7.27-7.49 (2H, m), 7.57 (1H, d, J=2.1 Hz), 7.74 (1H, m), 8.16 (1H, s).

NMR: 38) Compound of Example 332: NMR (CDCl₃) δ: 1.50 (3H, t, J=6.9 Hz),1.51 (3H, t, J=6.9 Hz), 3.93 (3H, s), 4.11-4.24 (4H, m), 6.95 (1H, d,J=8.2 Hz), 7.44-7.49 (3H, m), 8.34 (1H, s), 8.40 (1H, s), 11.19 (1H, s).

NMR: 39) Compound of Example 333: NMR (CDCl₃) δ: 1.49 (3H, t, J=7.0 Hz),1.51 (3H, t, J=7.0 Hz), 3.93 (3H, s), 4.02 (3H, s), 4.10-4.29 (4H, m),6.95 (1H, d, J=8.3 Hz), 7.05 (1H, d, J=8.7 Hz), 7.55 (1H, dd, J=2.0 Hz,8.3 Hz), 7.64 (1H, d, J=2.0 Hz), 7.86 (1H, s), 8.00 (1H, dd, J=2.3 Hz,8.7 Hz), 9.05 (1H, d, J=2.3 Hz).

NMR: 40) Compound of example 334: NMR (CDCl₃) δ: 1.00 (3H, t, J=7.3 Hz),1.01 (3H, t, J=7.3 Hz), 1.51-1.58 (4H, m), 1.81-1.90 (4H, m), 4.01 (3H,s), 4.03-4.17 (4H, m), 6.95 (1H, d, J=8.3 Hz), 7.09 (1H, d, J=8.7 Hz),7.33 (1H, s), 7.52 (1H, dd, J=2.1 Hz, 8.3 Hz), 7.60 (1H, d, J=2.1 Hz),8.06 (1H, dd, J=2.3 Hz, 8.7 Hz), 8.44 (1H, d, J=2.3 Hz).

NMR: 41) Compound of Example 335: NMR (CDCl₃) δ: 1.07 (3H, t, J=7.4 Hz),1.09 (3H, t, J=7.4 Hz), 1.83-1.96 (4H, m), 4.00-4.13 (4H, m), 4.01 (3H,s), 6.95 (1H, d, J=8.4 Hz), 7.09 (1H, d, J=8.8 Hz), 7.32 (1H, s), 7.52(1H, dd, J=2.2 Hz, 8.4 Hz), 7.60 (1H, d, J=2.2 Hz), 8.08 (1H, dd, J=2.2Hz, 8.8 Hz), 8.45 (1H, d, J=2.2 Hz), 10.86 (1H, s).

NMR: 42) Compound of Example 336: NMR (CDCl₃) δ: 1.54 (3H, t, J=7.0 Hz),3.94 (3H, s), 4.01 (3H, s), 4.26 (2H, q, J=7.0 Hz), 6.95 (1H, d, J=8.4Hz), 7.09 (1H, d, J=8.6 Hz), 7.32 (1H, s), 7.54 (1H, dd, J=2.0 Hz, 8.4Hz), 7.60 (1H, d, J=2.0 Hz), 8.09 (1H, dd, J=2.2 Hz, 8.6 Hz), 8.45 (1H,d, J=2.2 Hz), 10.86 (1H, s).

NMR: 43) Compound of Example 337: NMR (CDCl₃) δ: 0.88 (6H, t, J=6.4 Hz),1.27 (28H, brs), 1.40-1.63 (4H, m), 1.78-1.91 (45, m), 3.99 (3H, s),4.01-4.15 (4H, m), 6.93 (1H, d, J=8.4 Hz), 7.08 (1H, d, J=8.6 Hz), 7.30(1H, s), 7.51 (1H, dd, J=2.2 Hz, 8.4 Hz), 7.59 (1H, d, J=2.2 Hz), 8.07(1H, dd, J=2.2 Hz, 8.6 Hz), 8.43 (1H, d, J=2.2 Hz), 10.86 (1H, s).

NMR: 44) Compound of Example 338: NMR (CDCl₃) δ: 1.45 (3H, t, J=7.0 Hz),1.62 (3H, t, J=7.0 Hz), 4.01 (3H, s), 4.09 (2H, q, J=7.0 Hz), 4.22 (2H,q, J=7.0 Hz), 6.55 (1H, d, J=2.4 Hz), 6.61 (1H, dd, J=2.4 Hz, 8.8 Hz),7.08 (1H, d, J=8.8 Hz), 7.37 (1H, s), 8.10 (1H, dd, J=2.4 Hz, 8.8 Hz),8.46 (1H, d, J=8.8 Hz), 8.49 (1H, d, J=2.4 Hz), 10.84 (1H, s).

NMR: 45) Compound of Example 339: NMR (CDCl₃) δ: 1.07 (3H, t, J=7.5 Hz),1.50 (3H, t, J=6.8 Hz), 1.80-2.10 (2H, m), 4.00 (3H, s), 4.12-4.47 (4H,m), 6.95 (1H, d, J=8.4 Hz), 7.09 (1H, d, J=8.6 Hz), 7.31-7.49 (1H, m),7.50-7.77 (2H, m), 8.13-8.27 (1H, m), 8.45 (1H, s), 10.86 (1H, s).

NMR: 46) Compound of Example 340: NMR (CDCl₃) δ: 1.07 (3H, t, J=7.4 Hz),1.52 (3H, t, J=7.0 Hz), 1.85-1.96 (2H, m), 4.04 (2H, t, J=6.7 Hz), 4.25(2H, q, J=7.0 Hz), 6.95 (1H, d, J=8.3 Hz), 7.49-7.63 (5H, m), 8.16-8.20(1H, m), 8.34 (1H, s)

NMR: 47 ) Compound of Example 341: NMR (CDCl₃) δ: 1.05 (3H, t, J=7.1 Hz,1.43 (3H, t, J=7.0 Hz), 1.46 (3H, t, J=7.0 Hz), 4.02-4.22 (6H, m), 6.87(1H, d, J=8.4 Hz), 7.34-7.49 (3H, m), 7.58-7.62 (2H, m), 7.63-7.74 (1H,m).

NMR: 48) Compound of Example 342: NMR (CDCl₃) δ: 1.50 (3H, t, J=7.0 Hz),1.52 (3H, t, J=7.0 Hz), 3.54 (2H, d, J=6.6 Hz), 3.92 (3H, s), 4.12-4.26(4H, m), 5.09-5.18 (2H, m), 6.09-6.12 (1H, m), 6.96 (1H, d, J=8.3 Hz),7.45 (1H, d, J=2.0 Hz), 7.49 (1H, dd, J=2.0 Hz, 8.3 Hz), 7.54 (1H, s),7.84 (1H, d, J=2.2 Hz), 8.28 (1H, d, J=2.2 Hz), 12.84 (1H, s).

NMR: 49) Compound of Example 344: NMR (CDCl₃) δ: 1.42 (3H, d, J=7.0 Hz),1.50 (3H, t, J=7.0 Hz), 1.52 (3H, t, J=7.0 Hz), 4.00 (3H, s), 4.10-4.33(4H, m), 5.07-5.23 (2H, m), 6.03-6.25 (1H, m), 6.93 (1H, d, J=8.3 Hz),7.31 (1H, s), 7.50-7.66 (2H, m), 7.94 (1H, d, J=2.2 Hz), 8.33 (1H, d,J=2.3 Hz), 11.26 (1H, s).

NMR: 50 ) Compound of Example 345: NMR (CDCl₃) δ: 1.49 (3H, t, J=7.0Hz), 1.51 (3H, t, J=7.0 Hz), 1.78 (6H, d, J=6.7 Hz), 3.93 (3H, s),4.10-4.30 (4H, m), 4.68 (2H, d, J=6.3 Hz), 5.42-5.62 (1H, m), 6.92 (1H,d, J=8.4 Hz), 7.04 (1H, d, J=8.8 Hz), 7.34 (1H, s), 7.52 (1H, dd, J=2.1Hz, 8.3 Hz), 7.61 (1H, d, J=2.0 Hz), 8.10 (1H, dd, J=2.4 Hz, 8.7 Hz),8.36 (1H, d, J=2.3 Hz).

NMR: 51) Compound of Example 346: NMR (CDCl₃) δ: 1.49 (3H, t, J=7.0 Hz),1.49 (3H, t, J=7.0 Hz), 3.98 (3H, s), 4.05-4.30 (4H, m), 5.01 (1H, dd,J=1.2 Hz, 5.8 Hz), 5.08 (1H, s), 6.23-6.43 (1H, m), 6.92 (1H, d, J=8.4Hz), 7.30 (1H, s), 7.54 (1H, dd, J=2.1 Hz, 8.3 Hz), 7.61 (1H, d, J=2.0Hz), 8.10 (1H, d, J=2.2 Hz), 8.34 (1H, d, J=2.2 Hz), 11.60 (1H, s).

NMR: 52) Compound of Example 347: NMR (CDCl₃) δ: 1.49 (3H, t, J=6.9 Hz),i.51 (3H, t, J=6.9 Hz), 1.87 (3H, s), 3.94 (3H, s), 4.10-4.30 (4H, m),4.56 (2H, s), 5.03 (1H, brs), 5.22 (1H, brs), 6.91 (1H, d, J=8.4 Hz),7.02 (1H, d, J=8.8 Hz), 7.34 (1H, s), 7.52 (1H, dd, J=2.1 Hz, 8.4 Hz),7.61 (1H, d, J=2.1 Hz), 8.10 (1H, dd, J=2.4 Hz, 8.8 Hz), 8.39 (1H, d,J=2.4 Hz).

NMR: 53) Compound of Example 351: NMR (CDCl₃) δ: 1.53 (3H, t, J=7.0 Hz),3.92 (3H, s), 3.95 (3H, s), 4.21 (2H, q, J=7.0 Hz), 6.95 (1H, d, J=8.4Hz), 7.05 (1H, d, J=8.6 Hz), 7.45 (1H, d, J=2.1 Hz), 7.52 (1H, dd, J=2.1Hz, 8.4 Hz), 7.64 (1H, s), 7.95 (1H, dd, J=2.1 Hz, 8.6 Hz), 8.39 (1H, d,J=2.1 Hz), 12.66 (1H, s).

NMR: 54) Compound of Example 305: NMR (DMSO-d₆) δ: 1.38 (3H, t, J=7.0Hz), 1.40 (3H, t, J=6.9 Hz), 4.07-4.27 (4H, m), 6.81 (2H, s), 7.08 (1H,q, J=8.3 Hz), 7.48-7.58 (2H, m), 8.04 (1H, s), 14.77 (2H, s).

NMR: 55) Compound of Example 309: NMR (CDCl₃) δ: 1.50 (3H, t, J=7.0 Hz),1.51 (3H, t, J=7.0 Hz), 4.10-4.33 (4H, m), 6.44 (1H, dd, J=2.5 Hz, 8.5Hz), 6.52 (1H, d, J=2.5 Hz), 6.93 (1H, d, J=9.0 Hz), 7.29 (1H, s),7.42-7.57 (3H, m).

Example 352

In 10 ml of dimethylformamide were suspended 1 g of2-(3,4-diethoxyphenyl)-4-(4-hydroxy-3-methoxycarbonylphenyl)thiazole and0.35 g of potassium carbonate. The suspension was stirred at roomtemperature for 30 minutes. Thereto was added 0.46 g of methylbromoacetate. The mixture was stirred at the same temperature for 4hours. The solvent was removed by distillation. The residue wasextracted with 40 ml of dichloromethane. The extract was washed with 10ml of water and 10 ml of a saturated aqueous sodium chloride solution,dried over magnesium sulfate, and subjected to distillation to removethe solvent. The residue was recrystallized from diisopropyl ether toobtain 1.1 g of2-(3,4-diethoxyphenyl)-4-(4-methoxycarbonylmethoxy-3-methoxycarbonylphenyl)thiazole.

Colorless acicular crystals, M.p.: 96°-97° C.

In the same procedure as in Example 352 were obtained the compounds ofExamples 1, 6, 23, 26-81, 92, 94-96, 101-108, 112, 115, 118, 121, 124,125-128, 130-133, 135, 136, 154-165, 167-227, 229-234, 253-273, 275-307,309-316, 318-328 and 330-351, by using respective starting materials.

Example 353

A solution of 1 g of2-(3,4-diethoxyphenyl)-4-(4-allyloxy-3-methoxycarbonylphenyl)thiazole in25 ml of o-dichlorobenzene was refluxed for 15 hours with heating. Afterthe completion of a reaction, the solvent was removed by distillation.The residue was recrystallized from diisopropyl ether to obtain 1 g of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-allylphenyl)thiazole.

Colorless prismatic crystals, M.p.: 118°-119° C.

In the same procedure as in Example 353 were obtained the compounds ofExamples 262, 275, 277, 316, 342, 344, 346 and 348, by using respectivestarting materials.

Example 354

4.9 g of2-(3,4-diethoxyphenyl)-4-(4-dimethylaminothiocarbonyloxy-3-methoxycarbonylphenyl)thiazolewas stirred with heating, at 170° C. for 5 hours. The product waspurified by silica gel column chromatography (eluent: dichloromethane)and recrystallized from ethanol to obtain 2.83 g of2-(3,4-diethoxyphenyl)-4-(4-dimethylaminocarbonylthio-3-methoxycarbonylphenyl)thiazole.

Yellow powder, M.p.: 108°-109° C.

Example 355

1 ml of 10% potassium hydroxide was added to a solution of 250 mg of2-(3,4-diethoxyphenyl-4-(4-dimethylaminocarbonylthio-3-methoxycarbonylphenyl)thiazolein 5 ml of ethanol. The mixture was refluxed for 8 hours with heating.The solvent was removed by distillation. The residue was extracted with40 ml of hot ethyl acetate. The extract was made acidic with 10%hydrochloric acid, washed with 5 ml of water and 10 ml of a saturatedaqueous sodium chloride solution, and dried. The solvent was removed bydistillation. The residue was recrystallized from dioxane-ethanol toobtain 130 mg of2-(3,4-diethoxyphenyl)-4-(4-mercapto-2-carboxyphenyl)thiazole.

Light brown powder, M.p.: 283°-285° C.

Example 356

To a solution of 1 g of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-4-allylphenyl)thiazolein 20 ml of methanol and 20 ml of tetrahydrofuran were added 0.5 ml ofosmium tetroxide (a 4% aqueous solution) and 1.22 g of4-methylmorpholine N-oxide. The mixture was stirred at room temperaturefor 4 hours. The solvent was removed by distillation. The residue wasmixed with 50 ml of dichloromethane and 25 ml of water for phaseseparation. The organic layer was washed with 25 ml of a saturatedaqueous sodium chloride solution and dried. The solvent was removed bydistillation. The residue was purified by silica gel columnchromatography (eluent: dichloromethane/methanol=199/1) to obtain 860 mgof2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-(2,3-dihydroxypropyl)phenyl!thiazole.

¹ H-NMR (CDCl₃) δ: 1.50 (3H, t, J=6.9 Hz), 1.52 (3H, t, J=6.9 Hz),2.25-2.40 (1H, m), 2.59 (1H, d, J=5.3 Hz), 2.86-3.14 (2H, m), 3.45-3.80(2H, m), 4.01 (3H, s), 4.01 (1H, brs), 4.10-4.30 (4H, m), 6.93 (1H, d,J=8.3 Hz), 7.32 (1H, s), 7.54 (1H, dd, J=2.1 Hz, 8.3 Hz), 7.59 (1H, d,J=2.1 Hz), 8.02 (1H, d, J=2.2 Hz), 8.34 (1H, d, J=2.2 Hz), 11.40 (1H,s).

Example 357

To a solution of 2 g of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl)-4-hydroxy-5-allylphenyl)thiazolein ml of tetrahydrofuran and 15 ml of water were added 2.5 ml of osmiumtetroxide (a 4% aqueous solution) and 3.9 g of sodium metaperiodate. Themixture was stirred at room temperature for 14 hours. After thecompletion of a reaction, the solvent was removed by distillation. Theresidue was mixed with 60 ml of dichloromethane and ml of water forextraction and phase separation. The organic layer was dried andsubjected to distillation to remove the solvent. The residue waspurified by silica gel column chromatography (eluent: dichloromethane)to obtain 1.33 g of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-formylmethylphenyl)thiazole.

¹ H-NMR (CDCl₃) δ: 1.50 (3H, t, J=7.0 Hz), 1.52 (3H, t, J=7.0 Hz), 3.82(2H, d, J=1.8 Hz), 4.01 (3H, s), 4.10-4.30 (4H, m), 6.92 (1H, d, J=8.4Hz), 7.33 (1H, s), 7.54 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.59 (1H, d, J=2.1Hz), 8.02 (1H, d, J=2.2 Hz), 8.39 (1H, d, J=2.2 Hz), 9.81 (1H, t, J=1.8Hz), 11.20 (1H, s).

Example 358

111 mg of sodium boron hydride was added to a solution of 1.3 g of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-formylmethylphenyl)thiazolein 30 ml of methanol, with stirring under ice-cooling. The mixture wasstirred at the same temperature for 30 minutes. After the completion ofa reaction, the solvent was removed by distillation. The residue waspurified by silica gel column chromatography (eluent:dichloromethane/n-hexane=4/1) and recrystallized from diethyl ether toobtain 570 mg of 2-(3,4-diethoxyphenyl)-4-3-methoxycarbonyl-4-hydroxy-5-(2-hydroxyethyl)phenyl!-thiazole.

Light brown acicular crystals, M.p.: 113°-114° C.

Example 359

A solution of 1 g of potassium 3-2-(3,4-diethoxyphenyl)thiazole-4-yl!-6-acetylaminobenzoate in 50 ml ofwater and 10 ml of 30% potassium hydroxide was refluxed for 8 hours withheating. After the completion of a reaction, the solvent was removed bydistillation. The residue was made weakly acidic with 10% hydrochloricacid and extracted with 80 ml of ethyl acetate. The extract was washedwith 20 ml of a saturated aqueous sodium chloride solution, dried andsubjected to distillation to remove the solvent. The residue wasrecrystallized from ethyl acetate to obtain 168 mg of2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-aminophenyl)thiazole.

Yellow acicular crystals, M.p.: 228°-229° C.

The compound of Example 298 was obtained by using starting materials, inthe same procedure as in Example 359.

Example 360

2 g of potassium carbonate was added to a solution of 1.5 g of2-(3,4-diethoxyphenyl)-4-(2,4-dihydroxyphenyl)thiazole in 40 ml ofacetone. Thereto was added 40 g of dry ice under cooling at -78° C. Themixture was sealed in a tube and stirred at 150° C. for 18 hours. Thesolvent was distilled off. The residue was made weakly acidic with 100ml of ethyl acetate and 10% hydrochloric acid, and extraction and phaseseparation was conducted. The organic layer was washed with 30 ml of asaturated aqueous sodium chloride solution and dried. The solvent wasdistilled off. The residue was mixed with 40 ml of dichloromethane. Theinsoluble was collected by filtration, washed with a small amount ofdichloromethane, dried and recrystallized from ethyl acetate to obtain241 mg of2-(3,4-diethoxyphenyl)-4-(3-carboxy-4,6-dihydroxyphenyl)thiazole.

Light brown plate crystals, M.p.: 233°-234° C.

In the same procedure as in Example 360 were obtained the compounds ofExamples 190, 262, 275, 276, 277, 278, 282, 284-286, 288-293, 295, 297,299, 304, 305 and 308, by using respective starting materials.

Example 361

A suspension of 1 g of2-(3,4-diethoxyphenyl)-4-(3-ethyl-4-hydroxyphenyl)thiazole, 1 g ofparaformaldehyde and 1.1 g of dimethylamine hydrochloride in 20 ml ofethanol was stirred at 100° C. for 4 hours with heating. The solvent wasdistilled off. The residue was mixed with 20 ml of water and 30 ml ofethyl acetate for extraction and phase separation. The ethyl acetatelayer was extracted with 10% hydrochloric acid (20 ml×3). The combinedaqueous layer was made basic with 10% sodium hydroxide and extractedwith dichloromethane. The extract was washed with 20 ml of a saturatedaqueous sodium chloride solution, dried and subjected to distillation toremove the solvent. The residue was purified by silica gel columnchromatography (eluent: dichloromethane/methanol=49/1). The product wasdissolved in acetone, mixed with hydrochloric acid-methanol and heated.The resulting crystals were collected by filtration, dried andrecrystallized from acetone to obtain 117 mg of2-(3,4-diethoxyphenyl)-4-(3-ethyl-4-hydroxyphenyl)-5-dimethylaminomethylthiazoledihydrochloride.

Yellow powder, M.p.: 163°-168° C.

Example 362

A solution of 16 g of 2-(3,4-diethoxyphenyl)-4-(3-cyanophenyl)thiazolein 120 ml of ethanol and 90 ml of a 40% aqueous sodium hydroxidesolution was refluxed for 15 hours with heating. The reaction mixturewas mixed with water, made acidic with concentrated hydrochloric acidand extracted with ethyl acetate (200 ml×3). The extract was washed withwater (10 ml×3) and subjected to distillation to remove the solvent. Theresidue was recrystallized from ethanol to obtain 7 g of2-(3,4-diethoxyphenyl)-4-(3-carboxyphenyl)thiazole.

Light pink acicular crystals, M.p.: 192°-192.8° C.

Example 363

A catalytic amount of 5% Pd--C was added to a solution of 250 mg of2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-allylphenyl)thiazole in10 ml of methanol. The mixture was stirred in a hydrogen atmosphere atroom temperature for 6 hours. After the completion of a reaction, thereaction mixture was filtered. The filtrate was concentrated. Theresidue was recrystallized from ethanol to obtain 193 mg of2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-propylphenyl)thiazole.

White powder, M.p.: 179°-180° C.

The compounds of Examples 295, 302 and 319 were obtained in the sameprocedure as in Example 363 by using respective starting materials.

Example 364

A solution of 1 g of2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxyphenyl)thiazole in 5 ml ofacetic anhydride was stirred at 100° C. for 4 hours with heating. Thesolvent was distilled off. The residue was dissolved in 50 ml of ethylacetate. To the solution was added 10 ml of a saturated sodiumhydrogencarbonate solution, and phase separation was conducted. Theethyl acetate layer was made acidic with 10% hydrochloric acid, washedwith 10 ml of a saturated aqueous sodium chloride solution, dried andsubjected to distillation to remove the solvent. The residue wasrecrystallized from ethyl acetate to obtain 145 mg of2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-acetyloxyphenyl)thiazole.

White acicular crystals, M.p.: 178°-179° C.

Example 365

1.2 g of ethyl iodide and 1.5 g of potassium carbonate were added to asolution of 1.2 g of2-(3-methoxycarbonyl-4-hydroxyphenyl)-4-(3,4-dihydroxyphenyl)thiazole in20 ml of dimethylformamide. The mixture was stirred at room temperaturefor 14 hours. The solvent was removed by distillation. The residue wasmixed with 40 ml of chloroform and 40 ml of water. The mixture was madeacidic with 10% hydrochloric acid and phase separation was conducted.The organic layer was washed with 20 ml of a saturated aqueous sodiumchloride solution, dried and subjected to distillation to remove thesolvent. The residue was purified by silica gel column chromatography(eluent: dichloromethane/n-hexane=3/1) to obtain 400 mg of2-(3-methoxycarbonyl-4-hydroxyphenyl)-4-(3,4-diethoxyphenyl)thiazole.

NMR (CDCl₃) δ: 1.35-1.60 (6H, m), 3.94 (3H, s), 4.10-4.30 (4H, m), 5.73(1H, s), 6.90 (1H, d, J=8.3 Hz), 7.03 (1H, d, J=8.8 Hz), 7.30 (1H, s),7.48-7.65 (2H, m), 8.13 (1H, dd, J=2.3 Hz, 8.8 Hz), 8.41 (1H, d, J=2.3Hz).

In the same procedure as in Example 365 were obtained the compounds ofExamples 1, 6, 23, 26-81, 92, 94-96, 101-108, 112, 115, 118, 121, 124,125-128, 130-133, 135, 136, 154-165, 167-227, 229-234, 253-273, 275-307,309-316, 318-328 and 330-351, by using respective starting materials.

Example 366

In the same procedure as in Example 147 were obtained the compounds ofExamples 253, 257, 259, 261-263, 267, 269, 271, 275-278, 281, 282,284-296, 297-301, 303-306, 308, 312, 314-318 and 320, by usingrespective starting materials.

Example 367

The compound of Example 258 was obtained in the same procedure as inExample 148, by using starting materials.

Example 368

In the same procedure as in Example 235 were obtained the compounds ofExamples 268, 271, 272, 283, 285, 298, 300, 310 and 320, by usingrespective starting materials.

Examples 367-374

The compounds shown in Table 12 were obtained in the same procedures asin Example 1 and Example 138, by using respective starting materials.

                  TABLE 12                                                        ______________________________________                                         ##STR835##                                                                   ______________________________________                                        Compound of Example 367                                                        ##STR836##                                                                    ##STR837##                                                                   Crystal form:                                                                            light brown acicular                                                          (recrystallized from ethyl acetate-n-hexane)                       M.p.: 92-93° C.                                                        Compound of Example 368                                                        ##STR838##                                                                    ##STR839##                                                                   Crystal form:                                                                            white acicular                                                                (recrystallized from ethanol)                                      M.p.: 256.8-257.0° C.                                                  Form: free                                                                    Compound of Example 369                                                        ##STR840##                                                                    ##STR841##                                                                   Crystal form:                                                                            white powdery                                                                 (recrystallized from ethyl acetate-ethanol)                        M.p.: 236.6-238.0° C.                                                  Form: free                                                                    Compound of Example 370                                                        ##STR842##                                                                    ##STR843##                                                                   Crystal form:                                                                            light yellow acicular                                                         (recrystallized from ethanol)                                      M.p.: 197.8-199.3° C.                                                  Form: free                                                                    Compound of Example 371                                                        ##STR844##                                                                    ##STR845##                                                                   Crystal form:                                                                            white powdery                                                                 (recrystallized from ethanol)                                      M.p.: 182-184° C.                                                      Form: free                                                                    Compound of Example 372                                                        ##STR846##                                                                    ##STR847##                                                                   Crystal form:                                                                            yellow powdery                                                                (recrystallized from acetone-diethyl ether)                        M.p.: 111-114° C.                                                      Form: trihydrochloride 1/2 hydrate                                            Compound of Example 373                                                        ##STR848##                                                                    ##STR849##                                                                   Form: free                                                                    NMR: 56)                                                                      Compound of Example 374                                                        ##STR850##                                                                    ##STR851##                                                                   Form: free                                                                    NMR: 57)                                                                      ______________________________________                                    

56) NMR (DMSO-d₆) δ: 1.37 (3H, t, J=6.9 Hz), 1.39 (3H, t, J=6.9 Hz),3.82 (3H, s), 4.13 (4H, m), 7.09 (1H, d, J=8.4 Hz), 7.30 (1H, m), 7.48(1H, dd, J=2.0 Hz, 8.4 Hz), 7.58 (2H, m), 7.71 (1H, s), 12.10 (1H, brs).

57) NMR (CDCl₃) δ: 1.41-1.54 (9H, m), 4.07-4.26 (6H, m), 6.92 (1H, d,J=8.4 Hz), 7.49 (1H, dd, J=2.0 Hz, 8.4 Hz), 7.63 (1H, d, J=2.0 Hz),7.86-8.05 (2H, m), 8.20 (1H, s), 8.44 (1H, dd, J-1.0 Hz, 7.7 Hz).

Example 375

The compounds of Examples 368-371 were obtained in the same procedure asin Example 147, by using respective starting materials.

Example 376

The compound of Example 368 was obtained in the same procedure as inExample 363, by using starting materials.

Example 377

The compounds of Examples 367-374 were obtained in the same procedure asin Example 365, by using respective starting materials.

The compounds of Examples 378-452, shown in Table 13 were obtained inthe same procedures as in Example 1 and Example 138, by using respectivestarting materials.

                                      TABLE 13                                    __________________________________________________________________________     ##STR852##                                                                                                               Crystal form                      Example                                     (recrystallization                                                                        M.p.                                                                          (°C.)          No.  R.sup.1    R.sup.2                                                                         R.sup.3                   solvent)    (salt                 __________________________________________________________________________                                                            form)                 378                                                                                 ##STR853##                                                                              H                                                                                ##STR854##               Yellow powder (diethyl                                                                    93-94 (2 HCl)         379  "          H                                                                                ##STR855##               Yellow powder (acetone)                                                                   119-122 (3 HCl)       380                                                                                 ##STR856##                                                                              H                                                                                ##STR857##               Light yellow                                                                              203-205.6thanol)      381                                                                                 ##STR858##                                                                              H                                                                                ##STR859##               Light yellow powder (ethyl                                                    acetate)    188.4-190.4                                                                   (decomposed) (-)      382  "          H                                                                                ##STR860##               White powder (ethanol)                                                                    67-68 (-)             383  "          H                                                                                ##STR861##               White powder (ethanol)                                                                    108-109 (-)           384  "          H                                                                                ##STR862##               White powder (diethyl                                                                     99-100 (-)            385                                                                                 ##STR863##                                                                              H                                                                                ##STR864##               White acicular (diethyl                                                       ether-n-hexane)                                                                           94-95 (-)             386  "          H                                                                                ##STR865##               White powder (diethyl                                                                     69-71.4 (-)           387  "          H                                                                                ##STR866##               Dark yellow                                                                   acicular (acetone)                                                                        213-214 (I)           388  "          H                                                                                ##STR867##               Light brown powder (diethyl                                                   ether)      81.2-83.6 (-)         389                                                                                 ##STR868##                                                                              H                                                                                ##STR869##               White powder (ethanol-diethyl                                                 ether)      212-214 (HCl)         390  "          H                                                                                ##STR870##               White powder (ethanol)                                                                    126.8-128.8 (-)       391  "          H                                                                                ##STR871##               White powder (ethyl                                                                       206.8-208.6 (-)       392  "          H                                                                                ##STR872##               White acicular (n-hexane-ethyl                                                 acetate- dichloromethane)                                                                163.2-164.1 (-)       393                                                                                 ##STR873##                                                                              H                                                                                ##STR874##               White acicular (methanol)                                                                 123-124 (-)           394  "          H                                                                                ##STR875##               White acicular (ethyl                                                         acetate)    144-145 (-)           395  "          H                                                                                ##STR876##               Light brown prismatic (ethyl                                                  acetate)    171-172 (-)           396  "          H                                                                                ##STR877##               White powder (ethyl                                                                       216-217 (-)           397                                                                                 ##STR878##                                                                              H                                                                                ##STR879##               White acicular (ethyl                                                         acetate-n-hexane)                                                                         109-113 (-)           398  "          H                                                                                ##STR880##               Yellow powder (ethanol)                                                                   118.8-182.4                                                                   (decomposed) (-)      399  "          H                                                                                ##STR881##               White acicular (ethyl                                                         acetate)    180.8-182.2 (-)       400  "          H                                                                                ##STR882##               Yellow amorphous                                                                          242.5 (decomposed)                                                             (4 HCl)              401                                                                                 ##STR883##                                                                              H                                                                                ##STR884##               White acicular (diethyl                                                       ether-n-hexane)                                                                           216-217 (-)           402  "          H                                                                                ##STR885##               Yellow powder (diethyl                                                        ether-ethanol)                                                                            195 (decomposed)                                                              (2 HCl)               403                                                                                 ##STR886##                                                                              H                                                                                ##STR887##               Gray powder (acetic                                                           acid-water) 184-186 (decompose                                                            d) (HBr)              404                                                                                 ##STR888##                                                                              H                                                                                ##STR889##               Yellow acicular (ethanol)                                                                 104.8-108.8 (-)       405                                                                                 ##STR890##                                                                              H                                                                                ##STR891##               White acicular (ethyl                                                         acetate)    217-219 (-)           406  "          H                                                                                ##STR892##               Light yellow                                                                              189.8-191 (-)ol)      407  "          H                                                                                ##STR893##               White acicular (ethanol)                                                                  138.2-139 (-)         408  "          H                                                                                ##STR894##               White acicular (ethanol)                                                                  222-223 (-)           409                                                                                 ##STR895##                                                                              H                                                                                ##STR896##               White acicular (ethyl                                                         acetate-ethanol)                                                                          240-242 (-)           410  "          H                                                                                ##STR897##               Light yellow acicular (ethyl                                                  acetate)    222-223               411  "          H                                                                                ##STR898##               White powder (ethyl                                                                       215-216 (-)           412  "          H                                                                                ##STR899##               White acicular (ethyl                                                         acetate)    158-159 (-)           413                                                                                 ##STR900##                                                                              H                                                                                ##STR901##               White acicular (ethyl                                                         acetate)    140-141 (-)           414  "          H                                                                                ##STR902##               White powder (ethanol)                                                                    234.6-239.4                                                                   (HCl)                 415  "          H                                                                                ##STR903##               White powder (n-hexane)                                                                   75-76.5               416  "          H                                                                                ##STR904##               White acicular (ethyl                                                         acetate)    126.5-128 (-)         417                                                                                 ##STR905##                                                                              H                                                                                ##STR906##               White powder (ethyl                                                           acetate-n-hexane)                                                                         NMR.sup.58)  (-)      418  "          H                                                                                ##STR907##               White acicular (ethyl                                                         acetate)    159-161 (-)           419  "          H                                                                                ##STR908##               White acicular (ethyl                                                         acetate)    106-107 (-)           420  "          H                                                                                ##STR909##               White powder (ethyl                                                                       236.2-237.2 (-)       421                                                                                 ##STR910##                                                                              H                                                                                ##STR911##                                                 422  "          H                                                                                ##STR912##               White powder (ethyl                                                                       212-213 (-)           423  "          H                                                                                ##STR913##                           NMR.sup.59)           424  "          H                                                                                ##STR914##               Yellow powder (ethyl                                                                      210-212 (-)           425                                                                                 ##STR915##                                                                              H                                                                                ##STR916##                           NMR.sup.60)  (-)      426  "          H                                                                                ##STR917##               Light brown                                                                   granular (dimethylformamide)                                                              271-273 (-)           427  "          H                                                                                ##STR918##               Yellow powder (ethyl                                                                      260-261 (-)           428  "          H                                                                                ##STR919##                                                 429                                                                                 ##STR920##                                                                              H                                                                                ##STR921##                                                 430  "          H                                                                                ##STR922##               Yellow powder (ethanol)                                                                   202-203               431  "          H                                                                                ##STR923##               White powder (methanol)                                                                   254-255 (-)           432  "          H                                                                                ##STR924##                                                 433                                                                                 ##STR925##                                                                              H                                                                                ##STR926##                                                 434  "          H                                                                                ##STR927##               White acicular (ethyl                                                         acetate)    243-246 (-)           435  "          H                                                                                ##STR928##               Yellow acicular (ethanol)                                                                 243-244               436  "          H                                                                                ##STR929##               Light orange prismatic (ethyl                                                 acetate)    230.4-231.4 (-)       437                                                                                 ##STR930##                                                                              H                                                                                ##STR931##               Dark yellow prismatic (ethyl                                                  acetate-diethyl ether-n-hexane                                                )           11 164.6-165.5                                                                (-)                   438  "          H                                                                                ##STR932##               Light brown powder (ethyl                                                     acetate)    153.8-155.4 (-)       439  "          H                                                                                ##STR933##               White powder (ethyl                                                                       178-178.6 (-)         440  "          H                                                                                ##STR934##               Light yellow                                                                  powder (ethanol-diethyl                                                       ether)      220.8-223.4           441                                                                                 ##STR935##                                                                              H                                                                                ##STR936##               Brown powder (ethanol)                                                                    174.4-175.6 (-)       442  "          H                                                                                ##STR937##               White acicular (methanol-dieth                                                yl ether)   102.5-103.5 (-)       443  "          H                                                                                ##STR938##               White powder (ethanol)                                                                    112-113 (-)           444  "          H                                                                                ##STR939##               Colorless oily                                                                            NMR.sup.61)           445                                                                                 ##STR940##                                                                              H                                                                                ##STR941##               Light brown                                                                   acicular (ethanol)                                                                        93-94 (-)             446  "          H                                                                                ##STR942##               Light brown prismatic                                                         (methanol-dichloro- methane)                                                              144-145 NMR.sup.62                                                            )  (-)                447  "          H                                                                                ##STR943##               Brown oily  NMR.sup.63)  (-)      448  "          H                                                                                ##STR944##               Colorless oily                                                                            NMR.sup.64)           449                                                                                 ##STR945##                                                                              H                                                                                ##STR946##               White solid NMR.sup.65)           450  "          H                                                                                ##STR947##               White acicular (ethanol)                                                                  113-114 (-)           451  "          H                                                                                ##STR948##               Yellow acicular (ethyl                                                        acetate)    202-203 (-)           452  "          H                                                                                ##STR949##                           NMR.sup.66)           __________________________________________________________________________

Example 453

94 mg of sodium boron hydride was added, at 0° C., to a solution of 540mg of 4- 2-(3,4-diethoxyphenyl)-4-thiazole!-1-methylpyridinium iodide in60 ml of methanol. The mixture was stirred at room temperature for 15hours. After the completion of a reaction, the reaction mixture wasconcentrated. The residue was mixed with 100 ml of ethyl acetate andwashed with 50 ml of water. The ethyl acetate layer was dried oversodium sulfate and concentrated. The residue was recrystallized fromdiethyl ether to obtain 300 mg of2-(3,4-diethoxyphenyl)-4-(1-methyl-1,2,5,6-tetrahydropyridin-4-yl)thiazole

Light brown powder, M.p.: 81.2°-83.6° C.

Example 454

200 mg of lithium aluminum hydride was added, at 0° C., to a solution of1.92 g of 2-(3,4-diethoxyphenyl)-4-(2-ethoxycarbonyl-6-pyridyl)thiazolein 150 ml of tetrahydrofuran. The mixture was stirred in an argonatmosphere for 2 hours. The reaction mixture was mixed with 1 ml of asaturated sodium sulfate slution. The resulting mixture was stirred at0° C. for 30 minutes and filtered through Celite. The filtrate wasconcentrated. The residue was purified by silica gel columnchromatography and recrystallized from ethyl acetate-n-hexane to obtain360 mg of 2-(3,4-diethoxyphenyl)-4-(2-hydroxymethyl-6-pyridyl)thiazole.

White acicular, M.p.: 109°-113° C.

The compounds of Examples 412, 423 and 442 were obtained in the sameprocedure as in Example 454, by using respective starting materials.

Example 455

1.13 ml of triethylamine was dropwise added, at room temperature, to asolution of 1 g of2-(3,4-diethoxyphenyl)-4-(2-carboxy-6-pyridyl)thiazole, 245 mg ofdimethylamine hydrochloride and 515 mg of diethyl cyanophosphate in 15ml of dimethylformamide. The mixture was stirred at the same temperaturefor 3 hours. The reaction mixture was mixed with 20 ml of water. Theresulting mixture was extracted with 50 ml of dichloromethane threetimes. The dichloromethane layer was dried over sodium sulfate andconcentrated. The residue was recrystallized from n-hexane-ethylacetate-dichloromethane to obtain 800 mg of2-(3,4-diethoxyphenyl)-4-(2-dimethylaminocarbonyl-6-pyrdyl)thiazole.

White acicular, M.p.: 163.2°-164.1° C.

The compounds of Examples 379, 400 and 401 were obtained in the sameprocedure as in Example 455, using respective starting materials.

Example 456

730 Milligrams of2-(3,4-diethoxyphenyl)-4-(2-dimethylaminocarbonyl-6-pyridyl)thiazole wasdissolved in 15 ml of tetrahydrofuran at room temperature, then thissolution was dropwise added to a suspension of 70 mg of lithium aluminumhydride in 10 ml of diethyl ether, in an argon atmosphere so as torefluxing the reaction mixture. After the completion of the dropwiseaddition, refluxing was continued for a further 1 hour and 30 minutes.The reaction mixture was mixed with 50 ml of water. The resultingmixture was extracted with three 50-ml portions of dichloromethane. Thedichloromethane layer was concentrated. The residue was purified bysilica gel thin-layer chromatography. The resulting ethanol solution wasmixed with concentrated hydrochloric acid to obtain a hydrochloride. Thehydrochloride was recrystallized from a diethyl ether-ethanol mixedsolvent to obtain 60 mg of2-(3,4-diethoxyphenyl)-4-(2-dimethylaminomethyl-6-pyridyl)thiazoledihydrochloride as a yellow powder.

M.p.: 195° C. (decomposed).

Example 457

8.5 g of trifluoromethanesulfonic acid anhydride was added to a solutionof 10 g of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxyphenyl)thiazoledissolved in 100 ml of dichloromethane. Thereto was dropwise added 6 mlof triethylamine with stirring under ice-cooling. The reaction mixturewas stirred at room temperature for 2 hours. Thereto was added 40 ml ofwater for phase separation. The organic layer was dried and subjected todistillation to remove the solvent. The residue was recrystallized fromethanol to obtain 12.7 g of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-trifluoromethanesulfonyloxyphenyl)thiazoleas a white powder.

M.p.: 112°-113° C.

Example 458

In 5 ml of dimethylformamide was dissolved 600 mg of2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-methoxymethoxyphenyl)thiazole.Thereto was added 56 mg of sodium hydride and 290 mg of 1-bromononane.The mixture was stirred at room temperature for 14 hours. The solventwas removed by distillation. To the residue were added 80 ml ofdichloromethane and 30 ml of a 10% aqueous sodium hydroxide solution,and phase separation was conducted. The dichloromethane portion waswashed with 20 ml of a saturated aqueous sodium chloride solution, driedand subjected to distillation to remove the solvent. The residue wassubjected to silica gel column chromatography. There was obtained, fromthe dichloromethane layer, 340 mg of2-(3,4-diethoxyphenyl)-4-(3-nonyloxycarbonyl-4-methoxymethoxyphenyl)thiazoleas a colorless oily substance.

Properties: NMR⁶¹).

In the same procedure as in Example 458 were obtained the compounds ofExamples 382-385, 390, 398, 404, 407, 415, 443, 444, 445, 447-450 and452, by using respective starting materials.

Example 459

In a mixed solvent consisting of 2 ml of dimethylformamide and 0.2 ml ofwater were dissolved 200 mg of2-(3,4-diethoxyphenyl)-4-chloromethylthiazole, 73 mg of 2-acetylpyrrole,200 mg of sodium iodide and 200 mg of sodium hydroxide. The solution wasstirred at 80° C. for 4 hours. The reaction mixture was subjected todistillation to remove the solvent. To the residue were added 30 ml ofdichloromethane and 20 ml of water, and phase separation was conducted.The organic layer was washed with 15 ml of a saturated aqueous sodiumchloride solution, dried and subjected to distillation to remove thesolvent. The residue was recrystallized from methanol to obtain 60 mg of2-(3,4-diethoxyphenyl)-4-(2-acetyl-1-pyrrolyl)methylthizaole as whiteacicular crystals.

M.p.: 123°-124° C.

Example 460

In 5 ml of dimethyl sulfoxide were dissolved 1 g of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-trifluoromethylsulfonyloxyphenyl)thiazoleand 0.73 g of 1-(2-aminoethyl)piperidine. The mixture was stirred at 80°C. for 5 hours. To the reaction mixture were added 40 ml of ethylacetate and 20 ml of water, and phase separation was conducted. Theorganic layer was washed with 15 ml of a saturated aqueous sodiumchloride solution, dried and subjected to distillation to remove thesolvent. The residue was purified by silica gel column chromatography(elutant: dichloromethane/methanol=49/1 by v/v) and dissolved in diethylether. The solution was mixed with hydrochloric acid-methanol to obtaina hydrochloride. The hydrochloride was recrystallized from diethyl etherto obtain 330 mg of 2-(3,4-diethoxyphenyl)-4-{(3-methoxycarbonyl-4-2-(1-piperidinyl)ethylamino!phenyl}thiazole dihydrochloride as a yellowpowder.

M.p.: 93°-94° C.

The compounds of Examples 389, 403, 433, 434 and 442 were obtained inthe same procedure as in Example 460, by using respective startingmaterials.

Example 461

In 20 ml of ethanol was dissolved 340 mg of 2-(3,4-diethoxyphenyl)-4-(3-nonyloxycarbonyl-4-methoxymethoxyphenyl)thiazole.Thereto was added 2 ml of 10% hydrochloric acid, and the mixture wasrefluxed for 20 minutes. The solvent was removed by distillation. To theresidue were added 40 ml of dichloromethane and 20 ml of water, andphase separation was conducted. The organic layer was washed with 15 mlof a saturated aqueous sodium chloride solution, dried and subjected todistillation to remove the solvent. The residue was recrystallized fromethanol to obtain 245 mg of2-(3,4-diethoxyphenyl)-4-(3-nonyloxycarbonyl-4-hydroxyphenyl)thiazole asa white powder.

M.p.: 67°-68° C.

In the same procedure as in Example 461 were obtained the compounds ofExamples 379, 380, 382-385, 395, 396, 411, 412, 417, 421-435, 445 and451 by using respective starting materials.

Example 462

In a mixed solvent consisting of 50 ml of methanol and 5 ml of waterwere suspended 1 g of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-allylphenyl)thiazole,50 mg of palladium acetate Pd(OAc)₂ ! and 230 mg of copper acetateCu(OAc)₂. H₂ O!. The suspension was stirred in an oxygen atmosphere at50° C. for 6 hours. 50 mg of palladium acetate was further added. After10 hours, 50 mg of palladium acetate was furthermore added. After 14hours, when no solid starting materials in the reaction mixture werevisible, the reaction mixture was filtered. The filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (eluent: dichloromethane/hexane=1/1 by v/v) andrecrystallized from methanol-dichloromethane to obtain 230 mg of2-(3,4-diethoxyphenyl)-4-(2-methyl-7-methoxycarbonyl-5-benzofuryl)thiazole.

Light brown prismatic, M.p.: 144°-145° C., NMR⁶²).

Example 463

In 20 ml of methanol was dissolved 1 g of 2-(3,4-diethoxyphenyl)-4-3-methoxymethoxymethoxycarbonyl-4-methoxymethoxy-5-(2-methyl-2-propenyl)phenyl!thiazole.Into the solution being stirred under ice-cooling was blown ozone. After1 hour, 0.5 ml of methyl sulfide was added. The mixture was stirred atthe same temperature for 30 minutes. The solvent was removed from thereaction mixture by distillation. To the residue were added 50 ml ofdichloromethane and 25 ml of water. The organic layer was separated,washed with 15 ml of a saturated aqueous sodium chloride solution, driedand subjected to distillation to remove the solvent. The residue waspurified by silica gel column chromatography (eluent:dichloromethane/n-hexane=2/3 by v/v) to obtain 500 mg of2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-acetylmethylphenyl)thiazoleas a colorless oily substance.

Properties: NMR⁶⁴).

The compound of Example 450 was obtained in the same procedure as inExample 463, by using starting materials.

Example 464

In 15 ml of ethanol was dissolved 220 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-acetylmethylphenyl)thiazole.Thereto was added 1 ml of 10% hydrochloric acid, and the mixture wasrefluxed for 2 hours with heating. The solvent was removed bydistillation. To the residue were added 20 ml of ethyl acetate and 10 mlof water, and phase separation was conducted. The organic layer waswashed with 10 ml of a saturated aqueous sodium chloride solution, driedand subjected to distillation to remove the solvent. The residue waspurified by silica gel column chromatography (eluent:chloroform/methanol=99/1 by v/v) and recrystallized from ann-hexane-ethyl acetate mixed solvent to obtain2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-acetylmethyl)thiazole asa white powder.

In the same procedure as in Example 467 were obtained the compounds ofExamples 379-385, 389, 391, 394-396, 399, 403, 411-414, 416-418,421-435, 445 and 451 by using respective starting materials.

Example 465

In 40 ml of o-dichlorobenzene was dissolved, with heating, 2 g of2-(3,4-diethoxyphenyl)-4-3-carboxy-4-hydroxy-5-(2-methyl-2-propenyl)Phenyl!-thiazole. Theretowere added about 10 mg of iodine and 1.5 g of potassium iodide (groundin a mortar), and the mixture was refluxed for 14 hours with heating.The reaction mixture was mixed with 30 ml of water and phase separationwas conducted. The organic layer was mixed with 30 ml of ethyl acetate.The mixture was washed with 20 ml of a saturated aqueous sodium chloridesolution, dried and subjected to distillation to remove the solvent. Theresidue was purified by silica gel column chromatography (eluent:dichloromethane) and recrystallized from diisopropyl ether to obtain 1 gof2-(3,4-diethoxyphenyl)-4-(2,2-dimethyl-7-carboxy-2,3-dihydrobenzofuran-5-yl)thiazoleas white powdery crystals.

M.p.: 106°-107° C.

Example 466

In a mixed solvent consisting of 100 ml of tetrahydrofuran and 40 ml ofwater was dissolved 3.7 g of 2-(3,4-diethoxyphenyl)-4-3-methoxymethoxycarbonyl-4-methoxymethoxy-5-(1-propenyl)phenyl!thiazole.To the solution were added 100 mg of osmium tetroxide (OsO₄) and 5.6 gof sodium periodate (NaIO₄), and the mixture was stirred at roomtemperature for 14 hours. The reaction mixture was filtered. Thefiltrate was concentrated to a 1/3 volume. To the concentrate was added100 ml of ethyl acetate, and phase separation was conducted. The organiclayer was washed with 40 ml of a saturated aqueous sodium chloridesolution, dried and subjected to distillation to remove the solvent. Theresidue was purified by silica gel column chromatography (elutant:dichloromethane) to obtain 600 mg of2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-formylphenyl)thiazole(compound A) and 1.28 g of 2-(3,4-diethoxyphenyl)-4-3-methoxymethoxycarbonyl-4-methoxymethoxy-5-(1,2-dihydroxypropyl)phenyl!thiazole(compound B). The 2-(3,4-diethoxyphenyl)-4-3-methoxymethoxycarbonyl-4-methoxymethoxy-5-(1,2-dihydroxypropyl)phenyl!thiazole(compound B) was dissolved in 40 ml of methanol. To the solution wereadded 5 g of sodium periodate (NaIO₄) and 10 ml of water, and themixture was stirred at room temperature for 14 hours. The solvent wasremoved from the reaction mixture by distillation. The residue was mixedwith 80 ml of ethyl acetate and 40 ml of water, and phase separation wasconducted. The organic layer was washed with 20 ml of a saturatedaqueous sodium chloride solution, dried and subjected to distillation toremove the solvent. The residue was combined with 600 mg of theabove-obtained2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-formylphenyl)thiazole(compound A). The mixture was recrystallized from ethanol to obtain 1.6g of2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxy-methoxy-5-formylphenyl)thiazoleas white acicular crystals.

M.p.: 113°-114° C.

The compound of Example 417 was obtained in the same procedure as inExample 466 by using starting materials.

The compounds of Examples 467-509, shown in Table 14 were obtained inthe same procedures as in Example 1 and Example 138, by using respectivestarting materials.

                                      TABLE 14                                    __________________________________________________________________________     ##STR950##                                                                                                                    Crystal form                 Example                                          (recrystallization                                                                    M.p.(°C.)                                                              N                    No.  R.sup.1     R.sup.2                                                                         R.sup.3                       solvent)                                                                              (salt                __________________________________________________________________________                                                             form)                467                                                                                 ##STR951## H                                                                                ##STR952##                   Yellow                                                                                NMR.sup.67) (-)      468  "           H                                                                                ##STR953##                   Reddish brown acicular                                                        (ethyl                                                                                122-124 (-)          469  "           H                                                                                ##STR954##                   Light yellow acicular                                                         (ethyl acetate-n-                                                             hexane) 166-167 (-)          470                                                                                 ##STR955## H                                                                                ##STR956##                   White acicular (ethyl                                                         acetate)                                                                              NMR.sup.68) (-)      471  "           H                                                                                ##STR957##                   Light brown                                                                           NMR.sup.69) (-)      472                                                                                 ##STR958## H                                                                                ##STR959##                   White acicular (ethyl                                                         acetate-n- hexane)                                                                    167-168 (-)          473                                                                                 ##STR960## H                                                                                ##STR961##                   White powder (ethanol)                                                                175-176 (-)          474                                                                                 ##STR962## H                                                                                ##STR963##                   Light yellow acicular                                                         (ethyl acetate-n-                                                             hexane) 106-107 (-)          475  "           H                                                                                ##STR964##                   Light yellow acicular                                                         (diisopropyl ether                                                                    89-90 (-)            476  "           H                                                                                ##STR965##                   White acicular (diethyl                                                       ether)  103-105 (-)          477  "           H                                                                                ##STR966##                   White acicular (diethyl                                                       ether)  107-108 (-)          478                                                                                 ##STR967## H                                                                                ##STR968##                   Colorless                                                                             NMR.sup.70) (-)      479  "           H                                                                                ##STR969##                   Colorless                                                                             NMR.sup.71) (-)      480  "           H                                                                                ##STR970##                   Colorless                                                                             NMR.sup.72) (-)      481  "           H                                                                                ##STR971##                   Yellow                                                                        granular (dichloromethane                                                     - ether)                                                                              179-181 (-)          482                                                                                 ##STR972## H                                                                                ##STR973##                   Colorless                                                                             NMR.sup.73) (-)      483  "           H                                                                                ##STR974##                   Yellow                                                                                NMR.sup.74) (-)      484  "           H                                                                                ##STR975##                   Yellow                                                                                94-96 (-)thanol)     485  "           H                                                                                ##STR976##                   Colorless                                                                             NMR.sup.75)          486                                                                                 ##STR977## H                                                                                ##STR978##                           NMR.sup.76)          487  "           H                                                                                ##STR979##                   White acicular (diisoprop                                                     yl ether)                                                                             92-93 (-)            488  "           H                                                                                ##STR980##                   White acicular (ethanol)                                                              125.8-127.8          489  "           H                                                                                ##STR981##                   Yellow                                                                        acicular (ethanol)                                                                    226.5-229 (-)        490                                                                                 ##STR982## H                                                                                ##STR983##                   White acicular (ethanol)                                                              152-154 (-)          491  "           H                                                                                ##STR984##                   Yellow                                                                                172.4-175.6                                                                   (HBr)                492  "           H                                                                                ##STR985##                   Yellow                                                                                237.2-238 (-)ol)     493  "           H                                                                                ##STR986##                           NMR.sup.77) (-)      494                                                                                 ##STR987## H                                                                                ##STR988##                   Gray powder (ethanol-                                                         dimethyl- formamide)                                                                  272-277              495  "           H                                                                                ##STR989##                   Yellow                                                                                215-215.8 (-)ol)     496  "           H                                                                                ##STR990##                   Yellow                                                                                204-205.4 (HBr))     497  "           H                                                                                ##STR991##                   Colorless                                                                             NMR.sup.78)          498                                                                                 ##STR992## H                                                                                ##STR993##                   White prismatic (ethyl                                                        acetate-n- hexane)                                                                    1.01.3-103 (-)       499  "           H                                                                                ##STR994##                   White powder (acetone)                                                                107-110 (-)          500  "           H                                                                                ##STR995##                   Yellow                                                                                NMR.sup.79)          501  "           H                                                                                ##STR996##                                                502                                                                                 ##STR997## H                                                                                ##STR998##                                                503  "           H                                                                                ##STR999##                                                504  "           H                                                                                ##STR1000##                  White acicular (ethyl                                                         acetate)                                                                              197-198 (-)          505  "           H                                                                                ##STR1001##                                               506                                                                                 ##STR1002##                                                                              H                                                                                ##STR1003##                                               507  "           H                                                                                ##STR1004##                          NMR.sup.80) (-)      508  "           H                                                                                ##STR1005##                          NMR.sup.81) (-)      509  "           H                                                                                ##STR1006##                          NMR.sup.82)          __________________________________________________________________________                                                             (HBr)            

Example 510

In 30 ml of methanol was dissolved 500 mg of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxymethoxy-5-formylphenyl)thiazole.Thereto was added 3 ml of a 30% methylamine solution. The mixture wasstirred at room temperature for 14 hours and at 70° C. for 1 hour.Thereto was added 530 ml of sodium boron hydride with stirring underice-cooling. The mixture was stirred at room temperature for 3 hours.The solvent was removed from the reaction mixture by distillation. Theresidue was mixed with 40 ml of ethyl acetate and 20 ml of water, andphase separation was conducted. The organic layer was washed with 10 mlof a saturated aqueous sodium chloride solution, dried and subjected todistillation to remove the solvent. The residue was subjected to silicagel chromatography (eluent: dichloromethane/methanol=49/1 by v/v). Fromthe eluate was obtained 150 mg of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxymethoxy-5-methylaminomethylphenyl)thiazole.

Colorless oily, Properties: NMR⁷³).

The compound of Example 402 was obtained in the same procedure as inExample 510, using starting materials.

Example 511

In 20 ml of methanol was suspended 300 mg of 2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-formylphenyl)thiazolewith stirring. Threto was added 26.5 mg of sodium boron hydride at 0° C.The mixture was stirred at room temperature for 1 hour. 26.5 mg ofsodium boron hydride was further added, and the resulting mixture wasstirred at the same temperature for 1 hour. The solvent was removed fromthe reaction mixture by distillation. To the residue were added 30 ml ofdichloromethane and 15 ml of water, and phase separation was conducted.The organic layer was washed with 10 ml of a saturated aqueous sodiumchloride solution, dried and subjected to distillation to remove thesolvent to obtain 300 mg of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxy-5-hydroxymethylphenyl)thiazole.

Yellow solid, Properties: NMR⁷⁴).

The compounds of Examples 397, 412, 423, 445 and 498 were obtained inthe same procedure as in Example 511, by using respective startingmaterials.

Example 512

500 mg of2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-formylphenyl)thiazolewas added to 20 ml of a solution of a newly prepared Wittig reagent(triethyl phosphonoacetate: 270 mg, sodium hydride: 48 mg) intetrahydrofuran. The mixture was stirred at room temperature for 4hours. The solvent was removed from the reaction mixture bydistillation. To the residue were added 20 ml of ethyl acetate and 15 mlof water, and phase separation was conducted. The organic layer waswashed with 10 ml of a saturated aqueous sodium chloride solution, driedand subjected to distillation to remove the solvent. The residue wasrecrystallized from ethanol to obtain 380 mg of2-(3,4-diethoxyphenyl)-4-3-methoxymethoxycarbonyl-4-methoxymethoxy-5-(2-ethoxycarbonylvinyl)phenyl!thiazole.

Yellow powder, M.p.: 94°-96° C.

The compounds of Examples 478, 485, 486, 501 and 501 were obtained inthe same procedure as in Example 512, by using respective startingmaterials.

Example 513

535 mg of methyltriphenylphosphonium bromide was suspended in 10 ml oftetrahydrofuran with stirring. Thereto was added 190 mg of potassiumtert-butoxide at -5° C., and the mixture was stirred at the sametemperature for 1 hour. Thereto was added 500 mg of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxymethoxy-5-formylphenyl)thiazole.The mixture was stirred at the same temperature for 2 hours and at roomtemperature for 1 hour. To the reaction mixture were added 30 ml ofethyl acetate and 20 ml of water, and phase separation was conducted.The organic layer was washed with 20 ml of a saturated aqueous sodiumchloride solution, dried and subjected to distillation to remove thesolvent. The residue was purified by silica gel column chromatography(eluent: dichloromethane/n-hexane=2/1 by v/v) to obtain 240 mg of2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-hydroxy-5-vinylphenyl)thiazole(A) and 120 mg of2-(3,4-diethoxyphenyl)-4-(3-methoxymethoxycarbonyl-4-methoxymethoxy-5-vinylphenyl)thiazole(B).

NMR data of compound (A): ¹ H-NMR (CDCl₃) δ: 1.49 (3H, t, J=7.0 Hz),1.51 (3H, t, J=7.0 Hz), 3.58 (3H, s), 3.95 (3H, s), 4.15 (2H, q, J=7.0Hz), 4.22 (2H, q, J=7.0 Hz), 5.08 (2H, s), 5.43 (1H, dd, J=1.1, 11.1Hz), 5.89 (1H, dd, J=17.7 Hz), 6.92 (1H, d, J=8.4 Hz), 7.17 (1H, dd,J=11.1, 17.7 Hz), 7.43 (1H, s), 7.54 (1H, dd, J=2.1, 8.4 Hz), 7.61 (1H,d, J=2.1 Hz), 8.29 (2H, d, J=1.3 Hz).

NMR data of compound (B): ¹ H-NMR (CDCl₃) δ: 1.49 (3H, t, J=7.0 Hz),1.51 (3H, t, J=7.0 Hz), 3.58 (3H, s), 3.59 (3H, s), 4.15 (2H, q, J=7.0Hz), 4.22 (2H, q, J=7.0 Hz), 5.10 (2H, s), 5.43 (1H, dd, J=1.1, 11.1Hz), 5.51 (2H, s), 5.89 (1H, dd, J=1.1, 17.1 Hz), 6.92 (1H, d, J=8.4Hz), 7.18 (1H, dd, J=11.1, 17.7 Hz), 7.43 (1H, s), 7.54 (1H, dd, J=2.1,8.4 Hz), 7.61 (1H, d, J=2.1 Hz), 8.29 (2H, d, J=1.3 Hz).

Example 514

In 10 ml of ethanol was dissolved 350 mg of 2-(3,4-diethoxyphenyl)-4-3-methoxymethoxycarbonyl-4-methoxymethoxy-5-(2-ethoxycarbonylvinyl)phenyl!thiazole.Thereto was added 0.2 ml of 10% hydrochloric acid. The mixture wasstirred at 60° C. for 1 hour with heating. Thereto was added 1 ml of 10%sodium hydroxide. The mixture was refluxed for 4 hours with heating. Thesolvent was removed from the reaction mixture by distillation. Theresidue was mixed with 15 ml of water. The mixture was made weaklyacidic with 10% hydrochloric acid and extracted with 40 ml of hot ethylacetate. The organic layer was washed with 15 ml of a saturated aqueoussodium chloride solution, dried and subject to distillation to removethe solvent. The residue was recrystallized from ethyl acetate to obtain170 mg of 2-(3,4-diethoxyphenyl)-4-3-carboxy-4-hydroxy-5-(2-carboxyvinyl)phenyl!thiazole.

Yellow powder, M.p.: 260°-261° C.

Example 515

In 20 ml of methanol was dissolved 150 mg of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-methoxymethoxy-5-methylaminomethylphenyl)thiazole.Thereto was added 0.2 ml of 10% hydrochloric acid. The mixture wasstirred at 60° C. for 30 minutes. 2 ml of 10% sodium hydroxide wasadded, and the mixture was refluxed for 1 hour with heating. Thereaction mixture was made neutral with 10% hydrochloric acid and thesolvent was removed by distillation. The residue was mixed with ethanol.The insoluble was collected by filtration, washed with water, dried andrecrystallized from dimethylformamide to obtain 35 mg of2-(3,4-diethoxyphenyl-4-(3-carboxy-4-hydroxy-5-methylaminomethylphenyl)thiazole.

Light brown granular, M.p.: 271°-273° C.

Example 516

A mixture of 500 mg of2-(3,4-diethoxyphenyl)-4-(4-cyano-pyridyl)thiazole, 20 ml of ethanol and17 ml of a 4% aqueous sodium hydroxide solution was refluxed for 16hours with heating. The reaction mixture was allowed to stand. Then, 200ml of water was added thereto. The mixture was extracted with 80 ml ofdichromethane two times. The aqueous layer was made acidic (pH=about 3)with concentrated hydrochloric acid and extracted with 150 ml of ethylacetate three times. The ethyl acetate layer was dried over anhydroussodium sulfate and concentrated. The residue was recrystallized fromethyl acetate to obtain 290 mg of2-(3,4-diethoxyphenyl)-4-(4-carboxy-2-pyridyl)thiazole.

White acicular crystals, M.p.: 236.2°-237.2° C.

Example 517

5.23 g of imidazole and 4.85 g of tert-butyldimethylchlorosilane wereadded, in this order, to a suspension of 4.02 g of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-hydroxyphenyl)thiazole in60 ml of dimethylformamide at room temperature. The mixture was stirredat the same temperature for 4 hours. To the reaction mixture were added100 ml of ice water and 200 ml of ethyl acetate. The organic layer wasseparated, washed with 100 ml of water and 50 ml of a saturated aqueoussodium chloride solution in this order, dried over anhydrous magnesiumsulfate and subjected to distillation to remove the solvent. The residuewas purified by silica gel column chromatography (eluent: n-hexane/ethylacetate=10/1) to obtain 5.14 g of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-tert-butyldimethylsilyloxyphenyl)thiazole.

Colorless oily substance, Properties.

Example 518

548 mg of lithium aluminum hydride was added to a solution of 5.43 g of2-(3,4-diethoxyphenyl)-4-(3-methoxycarbonyl-4-tert-butyldimethylsilyloxyphenyl)thiazolein 100 ml of tetrahydrofuran, with ice-cooling. The mixture was stirredat the same temperature for 7 hours. To the reaction mixture were added1.1 ml of water and 3 g of sodium sulfate. The resulting mixture wasfiltered through Celite. The filtrate was subjected to distillation toremove the solvent. To the residue were added 200 ml of ethyl acetateand 50 ml of water. The mixture was neutralized with 5N hydrochloricacid. The insoluble was removed by filtration. The filtrate wassubjected to phase separation. The organic layer was washed with 50 mlof water, dried over anhydrous magnesium sulfate and subjected todistillation to remove the solvent. The residue was purified by silicagel column chromatography (eluent: n-hexane/ethyl acetate=10/1 by v/v)and recrystallized from ethyl acetate-n-hexane to obtain 1.23 g of2-(3,4-diethoxyphenyl)-4-(3-hydroxymethyl-4-tert-butyldimethylsilyloxyphenyl)thiazole.

White prismatic crystals, M.p.: 101.3°-103° C.

The compounds of Examples 397, 412, 423, 445 and 483 were obtained inthe same procedure as in Example 518, by using respective startingmaterials.

Example 519

The following compound was obtained in the same procedures as inExamples 1 and 138, by using starting materials.

2-(3,4-Diethoxyphenyl)-4-3-carboxy-4-hydroxy-5-(1-isobutenyl)phenyl!thiazole

Properties: ¹ H-NMR (DMSO-d₆) δ: 1.38 (3H, t, J=6.9 Hz), 1.40 (3H, t,J=6.9 Hz), 1.86 (3H, s), 1.95 (3H, s), 4.12 (2H, q, J=6.9 Hz), 4.15 (2H,q, J=6.9 Hz), 6.33 (1H, brs), 7.09 (1H, d, J=8.7 Hz), 7.48-7.62 (2H, m),7.93 (1H, s), 7.95 (1H, d, J=2.1 Hz), 8.31 (1H, d, J=2.1 Hz).

Example 520

The following compounds were obtained in the same procedures as inExamples 1 and 138, by using respective starting materials.

4- 2-(3,4-Diethoxyphenyl)-4-thiazolyl!-pyridinium-1-oxide

Properties: ¹ H-NMR (DMSO-d₆) δ: 1.35 (3H, t, J6.9 Hz), 1.37 (3H, t,J=6.9 Hz), 4.07 (4H, m), 7.07 (1H, d, J=8.3 Hz), 7.52 (1H, dd, J=2.0 Hz,8.3 Hz), 7.58 (1H, d, J=2.0 Hz), 8.03 (2H, d, J=7.2 Hz), 8.29 (2H, d,J=7.2 Hz), 8.33 (1H, s).

2-(3,4-Diethoxyphenyl)-4-(2-cyano-4-pyridinium)thiazole

Properties: ¹ H-NMR (DMSO-d₆) δ: 1.36 (3H, t, J=6.9 Hz), 1.38 (3H, t,J=6.9 Hz), 4.08-4.23 (4H, m), 7.08 (11H, d, J=8.3 Hz), 7.55-7.61 (2H,m), 8.32 (1H, dd, J=1.3 Hz, 5.2 Hz), 8.64 (2H, s), 8.84 (1H, d, J=5.2Hz).

NMR data of the compounds of Examples 417, 423, 425, 444, 446-449, 452,467, 470, 471, 478-480, 482, 483, 485, 486, 493, 497, 500 and 507-509(NMR⁵⁸) -NMR⁸²))

NMR⁵⁸) : compound of Example 417, ¹ H-NMR (DMSO-d₆) δ: 1.38 (3H, t,J=7.0 Hz), 1.40 (3H, t, J=7.0 Hz), 2.22 (3H, s), 3.87 (2H, s), 4.08 (2H,q, J=7.0 Hz), 4.16 (2H, q, J=7.0 Hz), 7.10 (1H, d, J=8.2 Hz), 7.48-7.60(2H, m), 7.99 (1H, s), 8.08 (1H, d, J=2.3 Hz), 8.38 (1H, d, J=2.3 Hz).

NMR⁵⁹) : compound of Example 423, ¹ H-NMR (DMSO-d₆) δ: 1.38 (3H, t,J=6.9 Hz), 1.40 (3H, t, J=6.9 Hz), 4.11 (2H, q, J=6.9 Hz), 4.15 (2H, q,J=6.9 Hz), 4.60 (2H, s), 7.08 (1H, d, J=8.9 Hz), 7.45-7.63 (2H, m), 7.77(1H, s), 8.06 (1H, d, J=2.2 Hz), 8.34 (1H, d, J=2.2 Hz).

NMR⁶⁰) : compound of Example 425, ¹ -NMR (CDCl₃) δ: 1.48 (3H, t, J=7.0Hz), 1.50 (3H, t, J=7.0 Hz), 2.78 (2H, t, J=6.7 Hz), 3.09 (2H, t, J=6.7Hz), 4.07-4.30 (4H, m), 6.91 (1H, d, J=8.3 Hz), 7.52 (1H, d, J=8.3 Hz),7.60 (1H, brs), 8.02 (1H, brs), 8.38 (1H, brs).

NMR⁶¹) : compound of Example 444, ¹ H-NMR (CDCl₃) δ: 0.08-1.00 (3H, m),1.00-1.67 (1H, m), 1.67-1.95 (2H, m), 3.54 (3H, s), 4.16 (2H, q, J=7.0Hz), 4.23 (2H, q, J=7.0 Hz), 4.35 (2H, t, J=6.6 Hz), 5.30 (2H, s), 6.92(1H, d, J=8.4 Hz), 7.27 (1H, d, J=8.7 Hz), 7.36 (1H, s), 7.53 dd,.J=2.0Hz, 8.4 Hz), 7.62 (1H, d, J=2.0 Hz), 8.08 (1H, dd, J=2.3 Hz, 8.7 Hz),8.35 (1H, J=2.3 Hz).

NMR⁶²) : compound of Example 446, ¹ H-NMR (CDCl₃) δ: 1.50 (3H, t, J=7.0Hz), 1.52 (3H, t, J=7.0 Hz), 2.55 (3H, d, J=0.9 Hz), 4.04 (3H, s), 4.16(2H, q, J=7.0 Hz), 4.23 (2H, q, J=7.0 Hz), 6.50 d, J=1.0 Hz), 6.93 (1H,d, J=8.4 Hz), 7.45 (1H, s), 7.55 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.64 (1H,d, J=2.1 Hz), 8.34 (1H, d, J=1.8 Hz), 8.42 (1H, d, J=1.8 Hz).

NMR⁶³) : compound of Example 447, ¹ H-NMR (CDCl₃) δ: 1.49 (3H, t, J=7.0Hz), 1.51 (3H, t, J=7.0 Hz), 1.78 (3H, s), 3.54 (2H, s), 3.59 (3H, s),4.16 (2H, q, J=7.0 Hz), 4.22 (2H, q, J=7.0 Hz), 4.71 (1H, brs), 4.90(1H, brs), 5.09 (2H, s), 5.51 (2H, s), 6.92 (1H, d, J=8.4 Hz), 7.40 (1H,s), 7.53 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.61 (1H, d, J=2.1 Hz), 7.98 (1H,d, J=2.4 Hz), 8.34 (1H, d, J=2.4 Hz).

NMR⁶⁴) : compound of Example 448, ¹ H-NMR (CDCl₃) δ: 1.49 (3H, t, J=7.0Hz), 1.51 (3H, t, J=7.0 Hz), 2.24 (3H, s), 3.56 (3H, s), 3.59 (3H, s),3.95 (2H, s), 4.16 (2H, q, J=7.0 Hz), 4.22 (2H, q, J=7.0 Hz), 5.09 (2H,s), 5.50 (2H, S), 6.92 (1H, d, J=8.4 Hz), 7.42 (1H, s), 7.52 (1H, dd,J=2.1 Hz, 8.4 Hz), 7.60 (1H, d, J=2.1 Hz), 8.01 (1H, d, J=2.3 Hz), 8.39(1H, d, J=2.3 Hz).

NMR⁶⁵) : compound of Example 449, ¹ H-NMR (CDCl₃) δ: 1.50 (3H, t, J=7.0Hz), 1.51 (3H, t, J=7.0 Hz), 1.97 (3H, dd, J=1.6 Hz, 6.6 Hz), 3.58 (3H,s), 3.59 (3H, s), 4.16 (2H, q, J=7.0 Hz), 4.22 (2H, q, J=7.0 Hz), 5.09(2H, s), 5.50 (2H, s), 6.38 (1H, dd, J=15.9 Hz, 6.6 Hz), 6.83 (1H, d,J=15.9 Hz), 6.93 (1H, d, J=8.4 Hz), 7.42 (1H, s), 7.55 (1H, dd, J=2.1Hz, 8.4 Hz), 7.61 (1H, d, J=2.1 Hz), 8.23 (1H, d, J=2.2 Hz), 8.27 (1H,d, J=2.2 Hz).

NMR⁶⁶) : compound of Example 450, ¹ H-NMR (CDCl₃) δ: 1.16 (1.5H, d,J=6.3 Hz), 1.22 (1.5H, d, J=6.3 Hz), 1.43-1.57 (6H, m), 3.59 (3H, s),3.62 (3H, s), 4.05-4.36 (4H, m), 5.07-5.28 (2H, m), 5.30 (2H, s), 5.50(2H, s), 6.93 (1H, d, J=8.4 Hz), 7.45 (1H, s), 7.54 (1H, dd, J=2.1 Hz,8.4 Hz), 7.61 (1H, d, J=2.1 Hz), 8.21 (0.5H, d, J=2.3 Hz), 8.32 (0.5H,d, J=2.3 Hz), 8.48 (1H, m).

NMR⁶⁷) : compound of Example 467, ¹ H-NMR (CDCl₃) δ: 1.49 (3H, t, J=7.0Hz), 1.50 (3H, t, J=7.0 Hz), 3.49 (3H, s), 4.17 (2H, q, J=7.0 Hz), 4.19(2H, q, J=7.0 Hz), 5.28 (2H, s), 5.40 (2H, s), 6.91 (1H, d, J=8.4 Hz),7.22-7.70 (9H, m), 8.08 (1H, dd, J=2.4 Hz, 8.7 Hz), 8.40 (1H, d, J=2.4Hz).

NMR⁶⁸) : compound of Example 470, ¹ -NMR (CDCl₃) δ: 1.44-1.67 (12H, m),4.04 (3H, s), 4.10-4.33 (8H, m), 6.92 (2H, d, J=8.4 Hz), 7.37 (1H, s),7.46 (1H, s), 7.52-7.63 (3H, m), 7.66 (1H, d, J=2.0 Hz), 7.75 (2H, d,J=8.4 Hz), 8.08 (2H, d, J=8.4 Hz), 8.20 (1H, d, J=2.2 Hz), 8.46 (1H, d,J=2.2 Hz), 11.43 (1H, s).

NMR⁶⁹) : compound of Example 471, ¹ H-NMR (CDCl₃) δ: 1.50 (3H, t, J=7.0Hz), 1.53 (3H, t, J=7.0 Hz), 2.42 (3H, s), 3.96 (3H, s), 4.17 (2H, q,J=7.0 Hz), 4.23 (2H, q, J=7.0 Hz), 6.94 (1H, d, J=8.4 Hz), 7.54 (1H, dd,J=2.1 Hz, 8.4 Hz), 7.59 (1H, s), 7.60 (1H, d, J=2.1 Hz), 8.76 (1H, d,J=2.3 Hz), 8.80 (1H, d, J=2.3 Hz).

NMR⁷⁰) : compound of Example 478, ¹ H-NMR (CDCl₃) δ: 1.49 (3H, t, J=7.0Hz), 1.51 (3H, t, J=7.0 Hz), 3.59 (3H, s), 3.59 (2H, d, J=6.3 Hz), 3.94(3H, S), 4.16 (2H, q, J=7.0 Hz), 4.22 (2H, q, J=7.0 Hz), 5.08 (2H, s),5.07-5.17 (1H, m), 5.17-5.27 (1H, m), 5.96-6.16 (1H, m), 6.92 (1H, d,J=8.4 Hz), 7.40 (1H, s), 7.54 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.60 (1H, d,J=2.1 Hz), 7.98 (1H, d, J=2.4 Hz), 8.27 (1H, d, J=2.4 Hz).

NMR⁷¹) : compound of Example 479, ¹ H-NMR (CDCl₃) δ: 1.48 (3H, t, J=7.0Hz), 1.51 (3H, t, J=7.0 Hz), 3.55 (3H, s), 3.89 (2H, d, J=1.7 Hz), 3.94(3H, s), 4.15 (2H, q, J=7.0 Hz), 4.21 (2H, q, J=7.0 Hz), 5.09 (2H, s),6.91 (1H, d, J=8.4 Hz), 7.43 (1H, s), 7.52 (1H, dd, J=2.1 Hz, 8.4 Hz),7.59 (1H, d, J=2.1 Hz), 8.04 (1H, d, J=2.3 Hz), 8.36 (1H, d, J=2.3 Hz),9.79 (1H, t, J=1.7 Hz).

NMR⁷²) : compound of Example 480, ¹ H-NMR (CDCl₃) δ: 1.50 (3H, t, J=7.0Hz), 1.52 (3H, t, J=7.0 Hz), 3.60 (3H, s), 3.98 (3H, s), 4.16 (2H, q,J=7.0 Hz), 4.23 (2H, q, J=7.0 Hz), 5.22 (2H, s), 6.92 (1H, d, J=8.4 Hz),7.50 (1H, s), 7.54 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.60 (1H, d, J=2.1 Hz),8.57 (1H, d, J=2.5 Hz), 8.73 (1H, d, J=2.5 Hz), 10.50 (1H, s).

NMR⁷³) : compound of Example 482, ¹ H-NMR (CDCl₃) δ: 1.49 (1H, t, J=7.0Hz), 1.51 (3H, t, J=7.0 Hz), 2.50 (3H, s), 3.60 (3H, s), 3.92 (2H, s),3.94 (3H, s), 4.15 (2H, q, J=7.0 Hz), 4.22 (2H, q, J=7.0 Hz), 5.12 (2H,s), 6.92 (1H, d, J=8.4 Hz), 7.44 (1H, s), 7.54 (1H, dd, J=2.1 Hz, 8.4Hz), 7.60 (1H, d, J=2.1 Hz), 8.13 (1H, d, J=2.4 Hz), 8.37 (1H, d, J=2.4Hz).

NMR⁷⁴) : compound of Example 483, ¹ H-NMR (CDCl₃) δ: 1.50 (3H, t, J=7.0Hz), 1.52 (3H, t, J=7.0 Hz), 2.41 (1H, t, J=6.6 Hz), 4.01 (3H, s), 4.16(2H, q, J=7.0 Hz), 4.23 (2H, q, J=7.0 Hz), 4.82 d, J=6.6 Hz), 6.93 (1H,d, J=8.4 Hz), 7.34 (1H, s), 7.55 (1H, dd, J=2.0 Hz, 8.4 Hz), 7.60 (1H,d, J=2.0 Hz), 8.10 (1H, d, J=2.3 Hz), 8.40 (1H, d, J=2.3 Hz), 11.38 (1H,s).

NMR⁷⁵) : compound of Example 485, ¹ H-NMR (CDCl₃) δ: 1.49 (3H, t, J=7.0Hz), 1.51 (3H, t, J=7.0 Hz), 3.58 (3H, s), 3.95 (3H, s), 4.15 (2H, q,J=7.0 Hz), 4.22 (2H, q, J=7.0 Hz), 5.08 (2H, s), 5.43 (1H, dd, J=1.1 Hz,11.1 Hz), 5.89 (1H, dd, J=1.1 Hz, 17.7 Hz), 6.92 (1H, d, J=8.4 Hz), 7.17(1H, dd, J=11.1 Hz, 17.1 Hz), 7.43 (1H, s), 7.54 (1H, dd, J=2.1 Hz, 8.4Hz), 7.61 (1H, d, J=2.1 Hz), 8.27 (2H, d, J=1.3 Hz).

NMR⁷⁶) : compound of Example 486, ¹ H-NMR (CDCl₃) δ: 1.49 (3H, t, J=7.0Hz), 1.51 (3H, t, J=7.0 Hz), 3.58 (3H, s), 3.59 (3H, s), 4.15 (2H, q,J=7.0 Hz), 4.22 (2H, q, J=7.0 Hz), 5.10 (2H, s), 5.43 (1H, dd, J=1.1 Hz,11.1 Hz), 5.51 (2H, s), 5.89 (1H, dd, J=1.1 Hz, 17.7 Hz), 6.92 (1H, d,J=8.4 Hz), 7.18 (1H, dd, J=11.1 Hz, 17.7 Hz), 7.43 (1H, s), 7.54 (1H,dd, J=2.1 Hz, 8.4 Hz), 7.61 (1H, d, J=2.1 Hz), 8.29 (2H, d, J=1.3 Hz).

NMR⁷⁷) : compound of Example 493, ¹ H-NMR (DMSO-d₆) δ: 1.35 (3H, t,J=6.9 Hz), 1.37 (3H, t, J=6.9 Hz), 2.72 (3H, s), 4.11 (4H, m), 7.09 (1H,d, J=9.0 Hz), 7.57 (1H, dd, J=2.2 Hz, 9.0 Hz), 7.60 (1H, d, J=2.2 Hz),7.89 (1H, brs), 8.22 (1H, brs), 8.44 (1H, s), 8.70 (1H, d, J=2.0 Hz),9.27 (1H, d, J=2.0 Hz).

NMR⁷⁸) : compound of Example 497, ¹ H-NMR (CDCl₃) δ: 0.24 (6H, s), 1.03(9H, s), 1.49 (3H, t, J=7.0 Hz), 1.51 (3H, t, J=7.0 Hz), 3.91 (3H, s),4.15 (2H, q, J=7.0 Hz), 4.22 (2H, q, J=7.0 Hz), 6.91 (1H, d, J=8.3 Hz),6.95 (1H, d, J=8.5 Hz), 7.34 (1H, s), 7.51 (1H, dd, J=2.0 Hz, 8.3 Hz),7.62 (1H, d, J=2.0 Hz), 8.03 .(1H, dd, J=2.4 Hz, 8.5 Hz), 8.34 (1H, d,J=2.4 Hz).

NMR⁷⁹) : compound of Example 500, ¹ H-NMR (CDCl₃) δ: 1.49 (3H, t, J=7.0Hz), 1.51 (3H, t, J=7.0 Hz), 2.91 (6H, s), 3.94 (3H, s), 4.15 (2H, q,J=7.0 Hz), 4.22 (2H, q, J=7.0 Hz), 6.91 (1H, d, J=8.4 Hz), 6.99 (1H, d,J=8.8 Hz), 7.28 (1H, s), 7.52 (1H, dd, J=2.0 Hz, 8.4 Hz), 7.62 (1H, d,J=2.0 Hz), 7.97 (1H, dd, J=2.2 Hz, 8.8 Hz), 8.25 (1H, d, J=2.2 Hz).

NMR⁸⁰) : compound of Example 507, ¹ H-NMR (CDCl₃) δ: 1.49 (3H, t, J=7.0Hz), 1.51 (3H, t, J=6.9 Hz), 2.63 (3H, s), 4.10-4.27 (4H, m), 6.89 (1H,d, J=8.4 Hz), 7.48 (1H, dd, J=2.1 Hz, 8.4 Hz), 7.59-7.64 (3H, m), 7.74(1H, s), 8.53 (1H, d, J=5.2 Hz).

NMR⁸¹) : compound of Example 508, ¹ H-NMR (CDCl₃) δ: 1.45 (3H, t, J=7.0Hz), 1.49 (3H, t, J=7.0 Hz), 4.09 (2H, q, J=7.0 Hz), 4.17 (2H, q, J=7.0Hz), 6.89 (1H, d, J=8.4 Hz), 7.25-7.32 (1H, m), 7.42-7.46 (2H, m), 7.49(1H, dd, J=2.2 Hz, 8.4 Hz), 7.61 (1H, d, J=2.2 Hz), 7.81 (1H, s),8.08-8.15 (3H, m), 8.57 (1H, dd, J=0.6 Hz, 5.0 Hz), 9.20 (1H, dd, J=0.6Hz, 1.5 Hz), 12.11 (1H, brs).

NMR⁸²) : compound of Example 509, ¹ H-NMR (CDCl₃) δ: 1.47 (3H, t, J=7.0Hz), 1.50 (3H, t, J=7.0 Hz), 3.81 (3H, s), 4.10-4.24 (4H, m), 6.93 (1H,d, J=8.4 Hz), 7.46-7.55 (3H, m), 8.00 (1H, dd, J=1.6 Hz, 7.8 Hz), 8.21(1H, s), 8.74-8.76 (1H, m).

Example 521

The following compounds were obtained in the same procedures as inExamples 1 and 147, by using respective starting materials.

5-Ethoxycarbonyl-2-(α-bromoacetyl)pyrazine and 3,4-diethoxythiobenzamidewere subjected to the same reaction as in Example 1 and then to the samehydrolysis as in Example 147 to obtain2-(3,4-diethoxyphenyl)-4-(5-carboxy-2-pyrazyl)thiazole.

4-Ethoxycarbonyl-2-(α-bromoacetyl)pyrimidine and3,4-diethoxythiobenzamide were subjected to the same reaction as inExample 1 and then to the same hydrolysis as in Example 147 to obtain2-(3,4-diethoxyphenyl)-4-(4-carboxy-2-pyrimidyl)thiazole.

5-Ethoxycarbonyl-2-(α-bromoacetyl)pyrimidine and3,4-diethoxythiobenzamide were subjected to the same reaction as inExample 1 and then to the same hydrolysis as in Example 147 to obtain2-(3,4-diethoxyphenyl)-4-(5-carboxy-2-pyrimidyl)thiazole.

6-Ethoxycarbonyl-2-(α-bromoacetyl)pyrazine and 3,4-diethoxythiobenzamidewere subjected to the same reaction as in Example 1 and then to the samehydrolysis as in Example 147 to obtain2-(3,4-diethoxyphenyl)-4-(6-carboxy-2-pyrazyl)thiazole.

4-Ethoxycarbonyl-2-(α-bromoacetyl)pyrrole and 3,4- diethoxythiobenzamidewere subjected to the same reaction as in Example 1 and then to the samehydrolysis as in Example 147 to obtain2-(3,4-diethoxyphenyl)-4-(4-carboxy-2-pyrrolyl)thiazole.

4-Ethoxycarbonyl-2-(α-bromoacetyl)furan and 3,4- diethoxythiobenzamidewere subjected to the same reaction as in Example 1 and then to the samehydrolysis as in Example 147 to obtain2-(3,4-diethoxyphenyl)-4-(4-carboxy-2-furyl)thiazole.

5-Ethoxycarbonyl-3-(α-bromoacetyl)furan and 3,4- diethoxythiobenzamidewere subjected to the same reaction as in Example 1 and then to the samehydrolysis as in Example 147 to obtain2-(3,4-diethoxyphenyl)-4-(5-carboxy-3-furyl)thiazole.

4-Ethoxycarbonyl-2-(α-bromoacetyl)thiophene and3,4-diethoxythiobenzamide were subjected to the same reaction as inExample 1 and then to the same hydrolysis as in Example 147 to obtain2-(3,4-diethoxyphenyl)-4-(4-carboxy-3-thienyl)thiazole.

5-Ethoxycarbonyl-3-(α-bromoacetyl)thiophene and3,4-diethoxythiobenzamide were subjected to the same reaction as inExample 1 and then to the same hydrolysis as in Example 147 to obtain2-(3,4-diethoxyphenyl)-4-(5-carboxy-3-thienyl)thiazole.

5-Ethoxycarbonyl-2-(α-bromoacetyl)thiazole and 3,4-diethoxythiobenzamidewere subjected to the same reaction as in Example 1 and then to the samehydrolysis as in Example 147 to obtain2-(3,4-diethoxyphenyl)-4-(5-carboxy-2-thiazolyl)thiazole.

Preparation Example 1

    ______________________________________                                        2-(3,4-Dimethoxyphenyl)-4-(3,4-dihydroxycarbostyril-6-yl)-                                                5      mg                                         thiazole                                                                      Starch                      132    mg                                         Magnesium stearate          18     mg                                         Lactose                     45     mg                                         Total                       200    mg                                         ______________________________________                                    

Tablets each containing the above components in the above amounts wereproduced according to an ordinary method.

Preparation Example 2

    ______________________________________                                        2-(3,4-Dimethoxyphenyl)-4-(2-oxo-benzoxazol-5-yl)thiazole                                                 500    mg                                         Polyethylene glycol (m.w.: 4000)                                                                          0.3    g                                          Sodium chloride             0.9    g                                          Polyoxyethylene sorbitan monoleate                                                                        0.4    g                                          Sodium metabisulfite        0.1    g                                          Methylparaben               0.18   g                                          Propylparaben               0.02   g                                          Distilled water for injection                                                                             100    ml                                         ______________________________________                                    

The above parabens, sodium metabisulfite and sodium chloride weredissolved in the above distilled water with stirring at 80° C. Thesolution was cooled to 40° C. Therein were dissolved the presentcompound, the polyethylene glycol and the polyoxyethylene sorbitanmonoleate in this order. To the solution was added the distilled waterfor injection to obtain a desired final volume. The resulting solutionwas filtered through an appropriate filter paper and sterilized. 1 ml ofthe thus prepared solution was filled into each ampul to prepare aninjection.

PHARMACOLOGICAL TESTS

The pharmacological tests for present compounds were conducted accordingto the following methods.

(1) Activity for inhibiting the generation of superoxide radical (O₂ ⁻)in human neutrophilic leukocytes

Human neutrophilic leukocytes were prepared in accordance with themethod of M. Markert et al. (Methods in Enzymology, vol. 105; pp.358-365, 1984). That is, a whole blood obtained from a healthy adult andtreated by anticoagulation method was subjected to a dextran-hypotonictreatment to obtain leukocyte cells. The leukocyte cells were thensubjected to a density gradient ultracentrifugation by Ficoll-Paque toobtain a neutrophilic leukocyte fraction.

O₂ ⁻ generation was examined by the ferricytochrome C method inaccordance with the method of B. N. Cronstein et al. Journal ofExperimental Medicine, vol. 158, pp. 1160-1177 (1983)!. That is, 1×10⁻⁶cell of neutrophilic leukocytes were stimulated with 3×10⁻⁷ M ofN-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) at 37° C. in thepresence of 1.3 mg/ml of ferricytochrome C and 5 μg/ml of cytochalasin Bin a Hepes-buffered Hank's solution (pH 7.4); the amount offerrocytochrome C formed by 4 minutes of reduction was determined bymeasuing an absorbance at a wavelength of 550 nm using aspectrophotometer; an absorbance in the presence of 25.1 μg/ml ofsuperoxide dismutase (SOD) was also measured; the difference of the twoabsorbances was taken as the amount of superoxide radical (O₂ ⁻)generated. Each test compound was dissolved in dimethyl sulfoxide(DMSO); the solution was added to neutrophilic leukocytes before theaddition of FMLP; then, the neutrophilic leukocytes were pre-incubatedat 37° C. By using the amount of superoxide radical (O₂ ⁻) generatedwhen the test compound solution was added and the amount of superoxideradical (O₂ ⁻) generated when only the solvent (DMSO) was added, a ratioof inhibition (%) was calculated, and the activity for inhibitingsuperoxide radical (O₂ ⁻) generation was expressed as 50% inhibitoryconcentration (IC₅₀).

TEST COMPOUNDS

1. 2-(3-Pyridyl)-4-phenylthiazole-1/4 ferrous chloride salt

2. 2-(3,4-Dimethoxyphenyl)-4-phenylthiazole

3. 2,4-Di(3-pyridyl)thiazole

4. 2-(3-Pyridyl)-4-methyl-5-ethoxycarbonylthiazole hydrochloride

5. 2-(2,4-Dimethoxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole

6. 2-(2-Pyridon-3-yl)-4-phenylthiazole

7. 2-(3,4-Dimethoxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole

8. 2-(3,4-Dimethoxyphenyl)-4-(3,4-dihydroxyphenyl)thiazole hydrochloride

9. 2-(4-Pyridyl)-4-(3,4-dihydroxyphenyl)thiazole hydrochloride

10. 2-(3-Thienyl)-4-(3,4-dihydroxyphenyl)thiazole

11. 2-(2-Thienyl)-4-(3,4-dihydroxyphenyl)thiazole

12. 2-(4-Oxo-1,4-dihydroquinolin-3-yl)-4-(3,4-dihydroxy-phenyl)thiazole

13. 2-(Pyrazin-2-yl)-4-(3,4-dihydroxyphenyl)thiazole

14. 2-(3,4-Dihydroxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazolehydrobromide

15. 2-(Carbostyril-3-yl)-4-(3,4-dihydroxyphenyl)thiazole

16. 2-(Pyrrol-2-yl)-4-(3,4-dihydroxyphenyl)thiazole

17.2-(3,4-Dimethoxyphenyl)-4-(4-methyl-2H-1,4-benzothiazin-3(4H)-on-6-yl)thiazole

18. 2-(3,4-Dimethoxyphenyl)-4-(3-hydroxy-4-pentyloxyphenyl)-thiazole

19. 2-(3,4-Dimethoxyphenyl)-4-(4-methylsulfonylphenyl)thiazole

20. 2-Phenyl-4-(3,4-dihydroxyphenyl)thiazole hydrochloride

21. 2-(3,4,5-Trimethoxyphenyl)-4-(3,4-dihydroxyphenyl)thiazolehydrochloride

22. 2-(3,4-Methylenedioxyphenyl)-4-(3,4-dihydroxyphenyl)-thiazole

23. 2-(3,4-Dimethoxyphenyl)-4-(carbostyril-6-yl)thiazole

24.2-(3,4-Dimethoxyphenyl)-4-(7-hydroxy-3,4-dihydrocarbo-styril-6-yl)thiazole

25. 2-(3,4-Dimethoxyphenyl)-4-(2-oxyindol-5-yl)thiazole

26. 2-(3,4-Dihydrocarbostyril-6-yl)-4-(3,4-dihydroxyphenyl)-thiazolehydrochloride

27.2-(3,4-Dimethoxyphenyl)-4-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl-3thiazole

28.2-(3,4-Dimethoxyphenyl)-4-(3,4-dihydro-2H-1,4-benzoxazin-6-yl)thiazolehydrochloride

29. 2-(3,4-Dimethoxyphenyl)-4-(2-oxobenzimidazol-5-yl)thiazole

30.2-(3,4-Dimethoxyphenyl)-4-(3-oxo-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)thiazole

31. 2-(3,4-Dimethoxyphenyl)-4-(10-acetylphenothiazin-2-yl)thiazole

32. 2,4-Di(3,4-dimethoxyphenyl)thiazole

33. 2-(3,4-Dimethoxyphenyl)-4-(3-acetylamino-4-hydroxyphenyl)-thiazole

34. 2-(3,4-Dimethoxyphenyl)-4-(3,4-dihydrocarbostyril-7-yl)thiazole

35. 2-(3,4-Dimethoxyphenyl)-4-(2-oxobenzothiazol-6-yl)thiazole

36. 2-(3,4-Dimethoxyphenyl)-4-(2-oxobenzoxazol-5-yl)thiazole

37. 2-(3,4-Dimethoxyphenyl)-4-(3-amino-4-hydroxyphenyl)thiazoledihydrochloride

38.2-(3,4-Dimethoxyphenyl)-4-(1-methyl-3,4-dihydrocarbo-styril-7-yl)thiazole

39. 2-(3,4-Dimethoxyphenyl)-4-(3,5-dihydroxyphenyl)thiazole

40. 2-(3,4-Dimethoxyphenyl)-4-(2,5-dihydroxyphenyl)thiazole

41. 2-(3,4-Dimethoxyphenyl)-4-(2,6-dihydroxyphenyl)thiazole

42. 2-(3,4-Dimethoxyphenyl)-4-(2-oxo-3-methylbenzothiazol-6-yl)thiazole

43. 2-(3,4-Dimethoxyphenyl)-4-(3-nitro-4-acetylaminophenyl)thiazole

44.2-(3,4-Dimethoxyphenyl)-4-(1,3-dimethyl-2-oxobenzimidazol-5-yl)thiazole

45. 2-(3,4-Dimethoxyphenyl)-4-(2,4-dihydroxyphenyl)thiazole

46. 2-(3,4-Dimethoxyphenyl)-4-(3-nitro-4-chlorophenyl)thiazole

47. 2-(3,4-Dimethoxyphenyl)-5-(3,4-dihydrocarbostyril-6-yl)thiazole

48. 2-(3,4-Dimethoxyphenyl)-4-(3,4-diacetylaminophenyl)thiazole

49. 2-(3,4-Dimethoxyphenyl)-4-(2-oxo-3-methylbenzoxazol-5-yl)thiazole

50. 2-(3,4-Dimethoxyphenyl)-4-(3-nitrophenyl)thiazole

51. 2-(3,4-Dimethoxyphenyl)-4-(3,5-diamino-4-hydroxyphenyl)thiazole

52. 2-(3,4-Dimethoxyphenyl)-4-(3,5-dinitro-4-hydroxyphenyl)thiazole

53.2-(3-Methoxy-4-methylthiophenyl)-4-(3,4-dihydrocarbo-styril-6-yl)thiazole

54.2-(3-Methoxy-4-methylsulfinylphenyl)-4-(3,4-dihydrocarbo-styril-6-yl)thiazole

55. 2-(3,4-Dimethoxyphenyl)-4-(2-oxobenzoxazol-6-yl)thiazole

56. 2-(3-Pyridyl)-4-(4-fluorophenyl)thiazole-1/3 FeCl₂ salt

57.2-(3,4-Dimethoxyphenyl)-4-(2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-6-yl)thiazole

58. 2-(3,4-Dimethoxybenzoyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole

59. 2-(3,4-Diethoxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)thiazole

60. 2-(3,4-Dimethoxyphenyl)-4-(2-pyridyl)thiazole hydrochloride

61. 4-(3,5-Dihydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole

62. 4-(3-Carboxy-4-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole

63. 4-(4-Hydroxysulfonyloxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole

64. 4-(4-Hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole

65. 4-(3-Acetylamino-4-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole

66. 4-(4-Hydroxy-3-aminophenyl)-2-(3,4-diethoxyphenyl)thiazoledihydrochloride

67. 4-(4-Cyanophenyl)-2-(3,4-diethoxyphenyl)thiazole

68.4-(3,4-Dihydrocarbostyril-6-yl)-2-(4-methoxy-3-propoxy-phenyl)thiazole

69. 4-(4-Amidinophenyl)-2-(3,4-diethoxyphenyl)thiazole hydrochloride

70. 4-(2,4,6-Trihydroxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole

71. 4-(3,5-Diaminophenyl)-2-(3,4-dimethoxyphenyl)thiazoledihydrochloride

72. 4-(4-Aminophenyl)-2-(3,4-diethoxyphenyl)thiazole hydrochloride

73. 4-1-Hydroxy-1-(3,4-dimethoxyphenyl)methyl!-2-(3,4-diethoxyphenyl)thiazole

74. 4-4-Methoxy-3-(4-ethyl-1-piperazinyl)phenyl!-2-(3,4-dihydroxyphenyl)thiazoletrihydrochloride

75. 4-(4-Chlorophenyl)-2-(3,4-diethoxyphenyl)thiazole

76. 4-(3,4-Diacetyloxyphenyl)-2-(3-pyridyl)thiazole

77. Methyl 4-2-(3,4-dimethoxyphenyl)thiazol-4-yl!phenyl-β-D-glucopyranosidouronate

78. 2-(3,4-Diethoxyphenyl)-4-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)phenyl!thiazole

79. 4-(3,5-Diacetyloxyphenyl)-2-(3,4-diethoxyphenyl)thiazole

80. 4-(4-Hydroxy-3-methoxycarbonylphenyl)-2-(3,4-diethoxyphenyl)thiazole

81.4-(4-Methoxycarbonylmethoxy-3-methoxycarbonylphenyl)-2-(3,4-diethoxyphenyl)thiazole

82. 4-(4-Hydroxy-3-carbamoylphenyl)-2-(3,4-diethoxyphenyl)thiazole

83. 4-(3-Carboxy-4-hydroxy-5-allylphenyl)-2-(3,4-diethoxyphenyl)thiazole

84.4-{3-Carboxy-4-hydroxy-5-(2-methyl-2-propenyl)phenyl}-2-(3,4-diethoxyphenyl)thiazole

85.4-(3-Carboxy-4-hydroxy-5-methylphenyl)-2-(3,4-diethoxyphenyl)thiazole

86.4-(3-Methoxycarbonyl-4-hydroxyphenyl)-2-(3-methoxy-4-ethoxyphenyl)thiazole

87. 4-(3-Carboxyphenyl)-2-(3,4-diethoxyphenyl)thiazole

88. 4-(3-Carboxy-4-hydroxyphenyl)-2-(3-methoxy-4-ethoxyphenyl)thiazole

89.4-(3-Amino-4-hydroxy-5-methoxycarbonylphenyl)-2-(3,4-diethoxyphenyl)thiazole

90.4-(3-Carboxy-4-hydroxy-5-propylphenyl)-2-(3,4-diethoxyphenyl)thiazole

91. 4-(3-Carboxy-6-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole

92. 4-(3-Carboxy-4-hydroxyphenyl)-2-(3-ethoxy-4-methoxyphenyl)thiazole

93.4-(3-Carboxy-4-hydroxy-5-isobutylphenyl)-2-(3,4-diethoxyphenyl)thiazole

94.3-{3-Carboxy-4-hydroxy-5-(2-hydroxyethyl)phenyl}-2-(3,4-diethoxyphenyl)thiazole

95. 4-(3-Carboxy-4-amino-6-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole

96. 4-(3-Carboxy-4-aminophenyl)-2-(3,4-diethoxyphenyl)thiazole

97.4-(3-Carboxy-4-acetyloxyphenyl)-2-(3,4-diethoxyphenyl)-2-(3,4-diethoxyphenyl)thiazole

98. 4-(3-Ethyl-4-hydroxyphenyl)-2-(3,4-Diethoxyphenyl)thiazole

99.4-(3-Carboxy-4-hydroxyphenyl)-2-(3,4-diethoxyphenyl)-5-methylthiazole

100. 4-(3-Carboxy-4,6-dihydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole

101.4-(3-Methoxycarbonyl-5-nitro-6-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole

102.4-(3-Methoxycarbonyl-5-amino-6-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole

103.4-(3-Carboxy-5-allyl-6-hydroxyphenyl)-2-(3,4-diethoxy-phenyl)thiazole

104. 4-(3-Carboxy-6-hydroxyphenyl)-2-(3-ethoxy-4-methoxy-phenyl)thiazole

105. 4-(3-Carboxy-4-hydroxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole (acompound mentioned in Example 3 of Japanese Patent Publication No.15935/1971)

106. 4-(3-Carboxy-4-hydroxyphenyl)-2-phenylthiazole (a compoundmentioned in Example 2 of Japanese Patent Publication No. 15935/1971)

107. 4-(3-Carboxy-4-methoxyphenyl)-2-phenylthiazole (a compoundmentioned in Example 4 of Japanese Patent Publication No. 15935/1971)

108. 4-(3-Carboxy-4-methoxyphenyl)-2-benzylthiazole (a compoundmentioned in Example 9 of Japanese Patent Publication No. 15935/1971)

109. 4-(3-Carboxyphenyl)-2-(4-chlorophenyl)thiazole (a compound includedin Japanese Patent Publication No. 15935/1971)

110. 4-(3-Carboxy-5-hydroxyphenyl)-2-(3,4-diethoxyphenyl)thiazole (acompound included in Japanese Patent Publication No. 15935/1971)

111. 4-(3-Carboxy-4-hydroxyphenyl)-2-(3,4-dibutoxyphenyl)thiazole (acompound included in Japanese Patent Publication No. 15935/1971)

112. 4-(3-Carboxy-6-methoxyphenyl)-2-(3,4-diethoxyphenyl)thiazole (acompound included in Japanese Patent Publication No. 15935/1971)

113.4-(2-Hydroxy-3-amino-5-carboxyphenyl)-2-(3,4-diethoxy-phenyl)thiazolehydrochloride

114.4-(2-Hydroxy-3-propyl-5-carboxyphenyl)-2-(3,4-diethoxy-phenyl)thiazole

115. 4-(6-Carboxy-2-pyridyl)-2-(3,4-diethoxyphenyl)thiazole

116. 2-(3,4-Diethoxyphenyl)-4-phenylthiazole

117. 2-(3,4-Diethoxyphenyl)-4-{3-methoxycarbonyl-4-2-(1-piperidinyl)ethylamino!phenyl}thiazole dihydrochloride

118. 2-(3,4-Diethoxyphenyl)-4-4-hydroxy-3-(2-dimethylaminoethoxycarbonyl)phenyl!thiazoletrihydrochloride

119. 2-(3,4-Diethoxyphenyl)-4-(2-carboxy-5-pyrrolyl)thiazole

120.2-(3,4-Diethoxyphenyl)-4-(4-hydroxy-3-n-nonyloxy-carbonylphenyl)thiazole

121. 2-(3,4-Diethoxyphenyl)-4-(2-methoxycarbonyl-5-furyl)thiazole

122. 2-(3,4-Diethoxyphenyl)-4-(2-carboxy-5-furyl)thiazole

123.2-(3,4-Diethoxyphenyl)-4-(2-dimethylaminocarbonyl-6-pyridyl)thiazole

124. 2-(3,4-Diethoxyphenyl)-4-(2-acetyl-1-pyrrolyl)methylthiazole

125. 2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-methoxyphenyl)thiazole

126.2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-ethylphenyl)thiazole

127. 2-(3,4-Diethoxyphenyl)-4-(2-hydroxymethyl-6-pyrrolidyl)thiazole

128. 2-(3,4-Diethoxyphenyl)-4-2-(4-methyl-1-piperazinyl)carbonyl)-6-pyridyl!thiazole

129. 2-(3,4-Diethoxyphenyl)-4-(2-carboxy-5-thienyl)thiazole

130. 2-(3,4-Diethoxyphenyl)-4-(2-methyl-7-carboxy-5-benzofuryl)thiazole

131. 2-(3,4-Diethoxyphenyl)-4-(4-ethoxycarbonyl-2-thiazolyl)thiazole

132. 2-(3,4-Diethoxyphenyl)-4-(4-carboxy-2-thiazolyl)thiazole

133. 2-(3,4-Diethoxyphenyl)-4-(4-hydroxy-3-hydroxymethylphenyl)thiazole

134. 2-(3,4-Diethoxyphenyl)-4-(4-ethoxy-3-carboxyphenyl)thiazole

135. 2-(3,4-Diethoxyphenyl)-4-(3-carboxy-5-pyridyl)thiazolehydrochloride

136.2-(3,4-Diethoxyphenyl)-4-(3-n-butoxycarbonyl-4-n-butoxyphenyl)thiazole

137. 2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-n-butoxyphenyl)thiazole

138. 2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-n-propoxyphenyl)thiazole

139.2-(3,4-Diethoxyphenyl)-4-(2,2-dimethyl-7-carboxy-2,3-dihydrobenzofuran-5-yl)thiazole

140. 2-(3,4-Diethoxyphenyl)-4-3-carboxy-4-hydroxy-5-(1-propenyl)phenyl!thiazol

141. 2-(3,4-Diethoxyphenyl)-4-(2-methyl-3-carboxy-5-pyridyl)thiazole

142.2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-formylphenyl)thiazole

143. 2-(3,4-Diethoxyphenyl)-4-(3-carboxy-6-pyridyl)thiazole

144. 2-(3,4-Diethoxyphenyl)-4-(2-carboxy-5-pyridyl)thiazole

145.2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-bromophenyl)thiazole

146. 2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-dimethylaminophenyl)thiazole

147.2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-vinylphenyl)thiazole

The results are shown in Table 15. In Table are shown the results of thecomparative test between present compounds (test compound Nos. 62, 87,88, 91, 92 and 104) and prior art comounds.

                  TABLE 15                                                        ______________________________________                                        Test compound (No).                                                                       IC.sub.50 (μM)                                                                      Test compound (No.)                                                                         IC.sub.50 (μM)                          ______________________________________                                         1          1        21            0.5                                         2          0.08     22            0.3                                         3          1        23            0.4                                         4          0.5      24            0.3                                         5          0.3      25            1                                           6          0.7      26            0.8                                         7          0.3      27            1                                           8          0.05     28            1                                           9          0.5      29            0.07                                       10          0.4      30            0.05                                       11          0.3      31            0.1                                        12          1        32            0.08                                       13          0.4      33            0.04                                       14          1        34            1                                          15          0.3      35            0.05                                       16          0.5      36            0.03                                       17          0.3      37            0.07                                       18          1        38            0.5                                        19          0.5      39            0.01                                       20          0.4      40            0.03                                       41          0.2      61            0.003                                      42          0.08     62            0.01                                       43          0.4      63            0.03                                       44          0.04     64            0.04                                       45          0.3      65            0.06                                       46          1        66            0.06                                       47          1        67            0.07                                       48          1        68            0.08                                       49          0.07     69            0.1                                        50          0.4      70            0.2                                        51          0.3      71            0.2                                        52          0.2      72            0.2                                        53          0.4      73            0.2                                        54          0.8      74            0.3                                        55          0.07     75            0.6                                        56          1        76            0.6                                        57          0.3      77            0.8                                        58          1.0      78            1                                          59          0.08     79            0.0013                                     60          0.05     80            0.01                                       81          0.026    95            0.0087                                     82          0.06     96            0.023                                      83          0.04     97            0.1                                        84          0.02     98            0.083                                      85          0.08     99            0.72                                       86          0.033    100           0.048                                      87          0.0048   101           0.01                                       88          0.1      102           0.069                                      89          0.007    103           0.094                                      90          0.008    104           0.034                                      91          0.023    113           0.025                                      82          0.02     114           0.1                                        93          0.012    115           0.08                                       94          0.18                                                              116         0.37     136           0.13                                       117         0.46     137           0.11                                       118         0.56     138           0.14                                       119         0.024    139           0.1                                        120         0.49     140           0.0047                                     121         0.038    141           0.094                                      122         0.019    142           0.12                                       123         0.38     143           0.27                                       124         0.12     144           0.035                                      125         0.19     145           0.11                                       126         0.014    146           0.11                                       127         0.02     147           0.01                                       128         0.58                                                              129         0.82                                                              130         0.05                                                              131         0.19                                                              132         0.05                                                              133         0.0092                                                            134         0.13                                                              135         0.035                                                             ______________________________________                                    

                  TABLE 16                                                        ______________________________________                                                    Test compound (No.)                                                                       IC.sub.50 (μM)                                     ______________________________________                                        Present compound                                                                             62           0.01                                                             87           0.0048                                                           88           0.1                                                              91           0.023                                                            92           0.02                                                            104           0.034                                             Prior art compound                                                                          105           1.0                                                             106           NE                                                              107           NE                                                              108           NE                                                              109           NE                                                              110           0.66                                                            111           8.3                                                             112           8.7                                               ______________________________________                                         NE: Abbreviation of "not effective"-                                     

(2) Activity for inhibiting the generation of venticular arrhythmia inrat heart when the coronary artery was closed and then blood wasreperfused

There were used male rats of Spaque Dawley (SD) strain (7-10 week old,body weight: 250-350 g). Each test compound was administered at a doseof 33 μl/kg in a form dissolved in a physiological saline solution. Eachrat was anesthesized with pentobarbital and thoracotomized underartifical respiration; the descending branch before left coronary arterywas ligated with a piece of silk string for 10 minutes; then, the bloodwas reperfused and observation was made for 10 minutes. The incidence ofventicular arrhythmia was examined using a standard four-legs secondaryinduced cardiograph. A test compound was intravenously administered at adose of 1 mg/kg 5 minutes before the ligature of the coronary artery.

The results on the test compound-administered group and thephysiological saline solution-administered group as a control are shownin Table 17.

                  TABLE 17                                                        ______________________________________                                                  Duration of ventricular fibrillation                                Test compound                                                                             when blood reperfused (sec)                                                                    Motality (%)                                     ______________________________________                                        No. 37      16.6             20                                               Control group                                                                             89.9             60                                               ______________________________________                                         (physiological saline solution)                                          

(3) Activity for inhibiting the renal disturbances appearing when kidneywas in ischemia and then blood was reperfused

In this test were used male rats of SD strain (body weight: about 250 g)which had been fasted for 18 hours. Each test compound was administeredat a dose of 1 ml/kg of body weight, in a 20% or 40% solution dissolvedin DMF. The right kidney of each rat was enucleated; the artery bloodcirculation in the left kidney was shut down for 60 minutes; then, theblood was reperfused. Each test compound was intravenously administeredat a dose of 3 mg/kg 15 minutes before reperfusion, and blood drawingwas made from each rat 24 hours and 4 hours after reperfusion to measureblood plasma creatinine (mg/100 ml) using a cratinine test kitmanufactured by Wako Pure Chemical Industries, Ltd. and calculate"Mean±S.E." therefrom.

The results are shown in Table 18

                  TABLE 18                                                        ______________________________________                                        Test compound   24 hours  48 hours                                            ______________________________________                                        Control (20% DMF)                                                                             3.64 ± 0.44                                                                          3.37 ± 0.77                                      No. 8           2.21 ± 0.19                                                                          2.04 ± 0.40                                      Control (40% DMF)                                                                             3.30 ± 0.38                                                                          3.37 ± 0.72                                      No. 33          2.63 ± 0.47                                                                          1.76 ± 0.18                                      ______________________________________                                    

(4) Activity for inhibiting the heart muscle necrosis in rat caused byclogging of the coronary artery and subsequent blood reperfusion

Male rats of SD strain (7-10 week old, 250-350 g) were used in thistest. The activity of creatine phosphokinase (CPK) in tissue was used asan indication of heart muscle necrosis.

A test compound was dissolved in a small amount of 1N aqueous NaOHsolution, then diluted with a physiological saline solution, andadministered at a dose of 1 ml/kg of body weight. Each rat wasanesthetized with pentobarbital and thoracotomized under artificialrespiration; the descending branch before left coronary artery wasligated with a piece of silk string for 12 minutes; then, the blood wasreperfused. Thereafter, the thoracotomized chest was closed and the ratwas waken from anesthesia. 2 hours after reperfusion, the heart wasenucleated under anesthesia; only the ischemic area was homogenized; andthe activity of CPK contained therein was measured. The test compoundwas intravenously administered at a dose of 6 mg/kg 5 minutes beforeligature of the coronary artery.

The results on the NaOH/physiological saline solution-administered groupas a control and the compound-administered group are shown in Table 19.

                  TABLE 19                                                        ______________________________________                                                            Activity of creatine phosphokinase                                            in tissue (U/mg of protein)                                             n     Mean ± S.E.                                            ______________________________________                                        Control group       14.86 ± 0.89                                           Test compound No.                                                                           62     19.53 ± 1.56*                                         ______________________________________                                         *: p < 0.05 2way ANOVA ANALYSIS (comparison with control group)               n: Number of tests                                                       

The reduction in CPK activity in tissue was inhibited significantly.Hence, it is considered that the present compound inhibited thedisturbances of cell functions in heart caused by ischemia andsubsequent reperfusion.

We claim:
 1. A thiazole derivative represented by the general formula(A), ##STR1007## wherein R^(A) represents a hydrogen atom or a hydroxylgroup; R^(1A) and R^(2A) are each represents a methoxy group or anethoxy group; R^(3A) represents a hydrogen atom or a lower alkyl group;R^(A) is bonded at the 4- or 6-position in the phenyl ring; R^(1A) andR^(2A) should not be methoxy groups simultaneously, or a salt thereof.2. A thiazole derivative represented by the general formula (C),##STR1008## wherein R^(1C) represents a phenyl group which may have 1-3lower alkoxy groups as substituent(s) on the phenyl ring; R^(2C)represents a hydrogen atom. R^(3C) represents a group of the formula,##STR1009## (wherein R^(4C) represents a hydrogen atom, a lower alkylgroup, a phenyl-lower alkyl group or a lower alkoxy-substituted loweralkyl group; R^(5C) represents an amino group, a lower alkoxygroup-substituted lower alkyl group, an alkyl group, a nitro group, alower alkenyl group, a lower alkanoyl group, a lower alkenyl grouphaving halogen atoms, a phenyl-lower alkoxy group, a halogen atom or ahydroxyl group-substituted lower alkyl group; n represents 2), or a saltthereof.
 3. A thiazole derivative represented by the general formula,##STR1010## wherein R^(1D) represents a phenyl group which may have 1-3lower alkoxy groups as substituent(s) on the phenyl ring; R^(2D)represents a hydrogen atom; R^(3D) represents a group of the formula,##STR1011## (wherein R^(4D) represents a hydrogen atom or a lower alkylgroup; R^(5D) represents an amino group, a lower alkoxycarbonyl-loweralkoxy group, a nitro group, a lower alkenyloxy group, a loweralkoxy-substituted lower alkoxy group, a mercapto group, a loweralkanoyloxy group, an aminocarbonylthio group which may have a loweralkyl group as a substituent, an aminothiocarbonyloxy group which mayhave a lower alkyl group as a substituent, a carboxy-substituted loweralkoxy group or a lower alkylsulfonyloxy group which may have a halogenatom)!, or a salt thereof.
 4. The thiazole derivative according to claim2, wherein R^(4C) is a hydrogen atom, or a salt thereof.
 5. The thiazolederivative according to claim 2, wherein R^(4C) is a lower alkyl group,a phenyl-lower alkyl group or a lower alkoxy-substituted lower alkylgroup, or a salt thereof. 6.2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-hydroxyphenyl)-thiazole. 7.2(3,4-Diethoxyphenyl)-4-3-carboxy-4-hydroxy-5-(2-methyl-2-propenyl)phenyl!thiazole. 8.2-(3,4-Diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-methylphenyl)thiazole.9. A superoxide radical inhibitor containing a pharmaceuticallyacceptable carrier and as the active ingredient2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxyphenyl)thiazole.
 10. Asuperoxide radical inhibitor containing a pharmaceutically acceptablecarrier and as the active ingredient 2-(3,4-diethoxyphenyl)-4-3-carboxy-4-hydroxy-5-(2-methyl-2-propenyl)phenyl!thiazole.
 11. Asuperoxide radical inhibitor containing a pharmaceutically acceptablecarrier and as the active ingredient2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-methylphenyl)thiazole.12. A thiazole derivative or a salt thereof of the formula (I),##STR1012## wherein R^(I) represents a lower alkoxy group; R^(3I)represents a hydrogen atom or a lower alkyl group; R^(1I) and R^(2I)each represent an ethoxy group; and R^(I) is bonded at the 4- or 5-position in the phenyl ring.
 13. The thiazole derivative or a saltthereof of claim 12, wherein R^(I) is an alkoxy group having 1 to 4carbon atoms and R^(3I) is a hydrogen atom or an alkoxy group having 1to 4 carbon atoms.
 14. The thiazole derivative or a salt thereof ofclaim 12, wherein R^(I) is an alkoxy group having 1 to 4 carbon atomsand R^(3I) is a lower alkyl group. 15.2-(3,4-diethoxyphenyl)-4-(3-carboxy-5-methoxyphenyl)thiazole.
 16. Asuperoxide radical inhibitor containing a pharmaceutically acceptablecarrier and as the active ingredient a thiazole derivative or a saltthereof of claim
 12. 17. A superoxide radical inhibitor containing apharmaceutically acceptable carrier and as the active ingredient2-(3,4-diethoxyphenyl)-4-(3-carboxy-5-methoxyphenyl)thiazole.
 18. Athiazole derivative or a salt thereof of the formula ##STR1013## whereinR^(3I) is a hydrogen atom or a lower alkyl group; R^(K) represents alower alkoxy group; R^(M) represents a lower alkyl or a lower alkenylgroup; and R^(J) represents a phenyl group which may have assubstituents on the phenyl ring from 1-3 lower alkoxy groups.
 19. Asuperoxide radical inhibitor containing a pharmaceutically acceptablecarrier and as the active ingredient a thiazole derivative or a saltthereof of claim
 18. 20. A superoxide radical inhibitor containing apharmaceutically acceptable carrier and as the active ingredient athiazole derivative of claim
 1. 21. A superoxide radical inhibitorcontaining a pharmaceutically acceptable carrier and as the activeingredient a thiazole derivative of claim
 2. 22. A superoxide radicalinhibitor containing a pharmaceutically acceptable carrier and as theactive ingredient a thiazole derivative of claim 3.